TY - JOUR
AU - Naguro, Isao
AB - Abstract VCells are constantly exposed to various types of stress, and disruption of the proper response leads to a variety of diseases. Among them, inflammation and apoptosis are important examples of critical responses and should be tightly regulated, as inappropriate control of these responses is detrimental to the organism. In several disease states, these responses are abnormally regulated, with adverse effects. Apoptosis signal-regulating kinase (ASK) family members are stress-responsive kinases that regulate inflammation and apoptosis after a variety of stimuli, such as oxidative stress and endoplasmic reticulum stress. In this review, we summarize recent reports on the ASK family in terms of their involvement in inflammatory diseases, focussing on upstream stimuli that regulate ASK family members. ASK family, ER stress, inflammation, MAPK cascade, oxidative stress All organisms are exposed to various types of stress and need to respond appropriately to maintain homeostasis. Cells also maintain homeostasis at the level by regulating a system that senses each stimulus and evokes an appropriate response through various signalling pathways. As maintenance of homeostasis at the cellular level results in whole-body homeostasis, disruption of the regulating systems leads to a variety of diseases. When an organism is exposed to harmful stimuli or conditions such as infection or tissue injury, inflammation is triggered as an adaptive response to eliminate foreign substances and repair damaged tissues. Although this inflammatory response is essentially a proper defense mechanism, excessive inflammation is detrimental. Therefore, tight control of inflammation is critical for responding appropriately to harmful stimuli or conditions. Mitogen-activated protein kinase (MAPK) is a widely conserved family in all eukaryotes from yeast to mammals. Activated MAPKs phosphorylate downstream target proteins and promote diverse responses, including inflammation. MAPKs are activated through phosphorylation by MAPK kinases (MAP2Ks) that are activated by upstream MAP2K kinases (MAP3Ks). Apoptosis signal-regulating kinase (ASK) family members belong to the MAP3K family, members of which respond to various types of stress, such as oxidative stress and endoplasmic reticulum (ER) stress. In vertebrates, the ASK family consists of three isoforms: ASK1, ASK2 and ASK3 (1–3). Activity of the ASK family is regulated by a variety of molecular mechanisms that are known to be very important in the context of inflammation. In the last two decades, the ASK family has been extensively studied with regard to its regulatory mechanisms and relationship with inflammatory diseases. In this review, we summarize recent reports on the ASK family in terms of their involvement in inflammation. Considering that the regulatory mechanism of the ASK family varies depending on what stimulus cells are exposed, we categorize reports from a viewpoint of stimuli that alter ASK family activity. This review begins with a catalog of molecular mechanisms that alter ASK family activity, followed by a discussion of how these mechanisms are involved in inflammation through ASK family regulation. This information will be valuable for the future development of therapeutic strategies targeting the ASK family. Molecular Mechanisms of ASK Family Regulation ASK family members form homo- and hetero-oligomers in cells. Previous studies have designated three types of oligomers: the ASK1 homo-oligomer, ASK1/2 hetero-oligomer and ASK3 homo-oligomer (4–6). Oligomerization is important for autophosphorylation and transphosphorylation of ASK family members at a common Thr in the activation loop of the kinase domain (Thr838, Thr806 and Thr808 in human ASK1, ASK2 and ASK3, respectively), which is essential for their kinase activity (4, 5, 7). On the other hand, various ASK isoforms possess unique molecular mechanisms for kinase activity regulation. Considering that ASK1 was the first and most studied, we begin with the regulatory mechanisms of this family member. Regulation of ASK1 under oxidative stress Excessive oxidative stress has a detrimental effect on the body and is mainly caused by reactive oxygen species (ROS) production, inducing various diseases such as cancer and Alzheimer's disease (AD) (8, 9). ROS are produced not only by pathological conditions but also by various factors in daily life, such as ultraviolet radiation and smoking. Therefore, the body is constantly at risk of exposure to oxidative stress. On the other hand, ROS contribute to maintaining homeostasis of the body during viral infection and cancer pathology by inducing apoptosis of affected cells, which is one of the beneficial consequences of ROS production in inflammation (8, 1, 11). Oxidative stress is a known activator of ASK1 (Fig. 1, ①②③). Under basal conditions, thioredoxin (Trx) interacts with ASK1, suppressing its oligomerization and kinase activity and thus diminishing subsequent ASK1-dependent apoptosis (12). This interaction is dependent on the intracellular redox state; the interaction is stronger in the reduced state but is attenuated in the oxidized state. This is because the structure of Trx changes depending on the redox state, with only the reduced form being able to bind to ASK1. It has been shown that Cys32 of Trx is responsible for high-affinity binding with ASK1. Oxidation of Trx triggers the formation of disulphide bonds between Cys32 and Cys35 of Trx, which results in its dissociation from ASK1 (13). At the cellular level, ROS production by tumour necrosis factor (TNF) α stimulation and Toll-like receptor 4 (TLR4)-dependent innate immune responses have been reported to be associated with ASK1 activation (11, 14). NAD(P)H oxidase (Nox)1 and Nox4 produce ROS upon TNFα and TLR4 stimulation, respectively, which promotes the dissociation of ASK1 from Trx, leading to ASK1 activation (15, 16). In addition, Trx-interacting protein (TXNIP, also known as vitamin D3 upregulated protein 1) has been found to increase the activity of ASK1 by interfering with its interaction with Trx under oxidative stress (17). Fig. 1. Open in new tabDownload slide The regulatory mechanism of ASK1. Under basal conditions (①), ASK1 activity is suppressed by degradation through the ubiquitin-proteasome system and inhibitory proteins. Oxidative stress, ER stress and Ca2+ stimulation trigger changes in interacting molecules with ASK1 to enhance kinase activity (②). Notably, the TRAF family interacts with ASK1 under both oxidative and ER stress. The dotted inhibition line indicates that the inhibition is cancelled in a stimulus-dependent manner. Under the activation state (③), ASK1 forms homo- and hetero-oligomers with itself and ASK2, respectively, to phosphorylate the critical Thr in the kinase domain. The activity of ASK1 under oxidative stress is fine-tuned via oxidative stress-dependent ubiquitination and deubiquitination (④). Fig. 1. Open in new tabDownload slide The regulatory mechanism of ASK1. Under basal conditions (①), ASK1 activity is suppressed by degradation through the ubiquitin-proteasome system and inhibitory proteins. Oxidative stress, ER stress and Ca2+ stimulation trigger changes in interacting molecules with ASK1 to enhance kinase activity (②). Notably, the TRAF family interacts with ASK1 under both oxidative and ER stress. The dotted inhibition line indicates that the inhibition is cancelled in a stimulus-dependent manner. Under the activation state (③), ASK1 forms homo- and hetero-oligomers with itself and ASK2, respectively, to phosphorylate the critical Thr in the kinase domain. The activity of ASK1 under oxidative stress is fine-tuned via oxidative stress-dependent ubiquitination and deubiquitination (④). In contrast to Trx, TNF receptor-associated factor (TRAF) family interacts with and activates ASK1 by facilitating homophilic interaction of ASK1 under oxidative stress and ER stress (11, 18) (Fig. 1, ②③). TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6 reportedly interact with ASK1, and TRAF1, TRAF2 and TRAF6 are important in the process of inflammation (19). Under oxidative stress, interaction of TRAF2 and TRAF6 with ASK1 upon dissociation of Trx from ASK1 is required for activation of ASK1 (20). TRAF6 is responsible for ASK1 activation in innate immunity and ischaemic/reperfusion (I/R) injury (11, 21), and TRAF1 has recently been reported to interact with ASK1 in myocardial I/R injury. Furthermore, TRAF1 expression is upregulated by H2O2 stimulation, suggesting that TRAF1 may also regulate ASK1 under oxidative stress (22). Akt phosphorylates Ser83 and negatively regulates ASK1 (Fig. 1, ①②). This phosphorylation possibly alters the conformation and interaction pattern of ASK1 with TRAF2 (23). Additionally, Akt seems to suppress ASK1 in an indirect mechanism through ROS regulation. In human melanoma (A375) cells, downregulation of transforming growth factor (TGF)-β inhibits Akt activity, resulting in ROS production through Nox4, which leads to activation of ASK1 and causes cell death. This report implies that Akt suppresses ASK1 via inhibition of ROS production in some cancer cells (8). The 14-3-3 protein recognizes ASK1 phosphorylation at Ser966 and binds to ASK1 to represses its activity (24) (Fig. 1, ①②). IKK is known to repress ASK1 by phosphorylating Ser966 (25). It has been known that activation of Ste20/oxidant stress response kinase 1 under oxidative stress results in phosphorylation of 14-3-3ζ at Ser58, which facilitates dissociation of 14-3-3ζ from ASK1 (26). Dissociation of 14-3-3 from ASK1 has also been observed in activated astrocytes in gliosis, suggesting a role of 14-3-3-mediated ASK1 regulation in the context of brain inflammation (27). Recently, it has been reported that beta-transducin repeat-containing protein (β-TrCP) induces degradation of ASK1 via ubiquitination under basal conditions. Interestingly, elimination of β-TrCP increases the activity of caspase 3 under oxidative stress, suggesting that the amount of ASK1 in the basal state affects the outcomes of oxidative stress (28). Regulation of ASK1 via ubiquitination is also observed under oxidative stress. Roquin-2 induces ASK1 degradation by ubiquitinating ASK1 in a ROS-dependent manner. Knockdown of Roquin-2 causes sustained activation of ASK1 and cell death under H2O2 stimulation (29). In contrast, the deubiquitinating enzyme USP9X deubiquitinates and stabilizes ASK1 under oxidative stress. Oxidative stress-induced cell death is reduced in USP9X-deficient cells (30). These reports suggest that the regulation of activated ASK1 via ubiquitination/deubiquitination directly leads to apoptosis regulation (Fig. 1, ①④). Regulation of ASK1 under ER stress The ER is an important cellular organelle in which secretory and membrane proteins are produced. When the normal function of the ER is compromised in certain situations, such as hypoxia and inflammation, unfolded proteins accumulate. This condition is called ER stress. Under ER stress, cells trigger the unfolded protein response (UPR) to relieve it (31). The detection of unfolded proteins in the ER and initiation of UPR are regulated by the ER stress receptors IRE1, PERK and ATF6 (32). Among these, IRE1 is known to interact with ASK1. It has been reported that IRE1 binds to TRAF2 and ASK1, resulting in ASK1 activation and apoptosis (18) (Fig. 1, ②③). In polyQ disease, ER stress is one of the main causes of neuronal death, and this process involves activation of ASK1 by the formation of the IRE1–TRAF2–ASK1 complex (18). In addition, mutants of Cu/Zn-superoxide dismutase 1 (SOD1), which is known as a cause of familial amyotrophic lateral sclerosis (ALS), induce ER stress and activate the IRE1–TRAF2–ASK1 pathway (18, 33). These findings suggest that the IRE1–TRAF2–ASK1 pathway operates in ER stress. Recently, an interesting association between ASK1 and Akt under ER stress was reported (Fig. 1, ②③). As mentioned above, Akt inhibits ASK1 as an upstream regulator during oxidative stress. In glioma cells, Akt is suppressed by the indomethacin-induced activation of ASK1–p38 pathway, which relief ASK1 inhibition and further amplify ASK1 activity to trigger apoptosis. This report suggests that the positive loop maintaining the activity of ASK1 via Akt suppression is important for triggering apoptosis during indomethacin-induced ER stress (34). Regulation of ASK1 under Ca2+ signalling Ca2+, an important molecule in intracellular signalling, is involved in the regulation of ASK1 activity. We reported that Ca2+/calmodulin-dependent protein kinase II (CAMKII) phosphorylates and activates ASK1 in a Ca2+-dependent manner (Fig. 1, ②③). Furthermore, p38 is activated by ASK1 in this pathway. Notably, CAMKII is required only for Ca2+-dependent ASK1 activation but not for oxidative stress-dependent activation, suggesting that the CAMKII–ASK1–p38 pathway is specifically involved in Ca2+-dependent ASK1 activation (35). In the context of acquired immunodeficiency syndrome (AIDS), Nef, a key modulator of AIDS pathogenesis, induces formation of the Nef-CAMKII-ASK1 complex and inhibition of Ca2+-dependent CAMKII-ASK1 signalling, resulting in interference with p38 phosphorylation and apoptosis in Jurkat T cells (36). Regulation of ASK2 under oxidative stress Below, we briefly describe the regulation of ASK2. Although ASK2 is constitutively degraded in the absence of ASK1, it is stabilized via formation of a heteromeric complex with ASK1 that effectively activates MAP2Ks, such as MKK4 and MKK6. In the heteromeric complex with ASK1, ASK2 effectively activates JNK under oxidative stress. In addition, ASK2 phosphorylates and activates ASK1 (Fig. 1, ③). Hence, ASK1 and ASK2 regulate each other through distinct mechanisms (5). As mentioned above, the ASK1 homo-oligomer and ASK1-ASK2 hetero-oligomer can be detected in cells. Interestingly, these oligomers have different roles in innate immunity and cancer, as discussed below. Regulation of ASK3 under osmotic stress Finally, we focus on the regulation of ASK3. ASK3 is predominantly expressed in the kidney where wide range of osmotic environment is observed, and we found that the kinase activity of ASK3 is altered by osmotic stress (7). Osmotic stress is caused by the difference between intracellular and extracellular osmolarity, leading to alterations in cell volume. ASK3 shows a bidirectional response to osmotic stress, being activated under hypoosmotic condition but inactivated under hyperosmotic condition (7). Moreover, phosphorylation at Thr808 (the critical site for activity) did not occur for a kinase-negative mutant of ASK3 under hypoosmotic conditions, suggesting that ASK3 is activated by autophosphorylation. We also reported that PP6 interacts with ASK3 depending on osmolarity and inhibits ASK3 by dephosphorylating Thr808. This interaction becomes stronger under hyperosmotic conditions and weaker under hypoosmotic conditions (37). Under osmotic stress, overexpressed ASK1 is activated by both hypoosmotic and hyperosmotic conditions (7). Thus, ASK1 and ASK3 appear to be regulated by different mechanisms under osmotic conditions. In an acute organ inflammation model, we found that ASK3-KO mice exhibit mild symptoms, though the precise mechanism is unknown (unpublished data). As recent reports suggest that high Na+ conditions in the body affect the inflammatory status through the regulation of immune cell differentiation (38–40), it would be interesting to investigate whether ASK3 is involved in the inflammatory response by sensing osmotic conditions in the body. Involvement of ASK Family in Inflammation The ASK family plays several roles in inflammation via various regulatory mechanisms that vary depending on the organ and disease. We next summarize the regulation and role of the ASK family in terms of the pathogenesis of inflammatory diseases. NAFLD/NASH Nonalcoholic fatty liver disease (NAFLD) comprises nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL has a benign course without progression, whereas NASH can progress to cirrhosis and liver cancer. NAFLD affects 20–30% of the world's population, and mortality rates are rising. Although therapeutic lifestyle modifications are currently the main treatment option, pharmacological treatments for NASH, which would be helpful, are being challenged. The pathology of NASH involves four stages: steatosis, hepatitis, fibrosis and hepatocellular cancer (HCC). In hepatitis, oxidative stress triggers inflammation and apoptosis. Therefore, inhibition of ASK1 is considered as a therapeutic target (41). In fact, hepatocyte-specific ASK1 deletion largely suppresses high-fat diet (HFD)-induced steatohepatitis (42). In addition, selonsertib, an ASK1 inhibitor, was tested in a Phase III clinical trial (43). Despite results that were not promising, two other NASH treatments using selonsertib are in Phase II clinical trials. Additionally, considering many NASH models described below suggest an association between ASK1 and hepatitis, there is still potential of ASK1 inhibitors to be used for the treatment of NASH. In constitutively activated NOD-like receptor protein 3 (NLRP3)-mutant mice, which develop fibrosis and hepatitis, ASK1 inhibition decreased both hepatocyte cell death and fibrosis by reducing hepatic expression of fibrogenic genes involved in collagen synthesis and matrix deposition (44). Thus, it was suggested that ASK1 promotes hepatocyte cell death and fibrosis in hepatic inflammation. In the liver of OXLAM-fed mice, one of the NASH models, oxidative stress increases, followed by upregulation of TXNIP, ASK1 activation and apoptosis. Induction of NLRP3 and activation of caspase-1 were also observed in the model (45) (Table I). Given that ASK1 is involved in the progression of hepatitis under NLRP3 signalling (44), ASK1 may also contribute to NASH development downstream of NLRP3 in OXLAM-fed mice. Table I. The relevance between ASK family and stimulation in each disease Diseases . Organ/cell . Stimulation (related molecules) . Oxidative stress . ER stress . Ca2+ stimulation . NASH Hepatocyte [ASK1/TXNIP] Schuster et al. (45) Innate immunity  Bacteria Raw264.7 cell [ASK1/TLR4, Nox4, Trx, TRAF6] Matsuzawa et al. (11)  AIDS Jurkat-T cell [ASK1/Nef, Trx] Geleziunas et al. (56) [ASK1/Nef, CaMKII] Kumar et al. (36) Autoimune diseases  RA FLS [ASK1/TLR4] Philippe et al. (58)  MS Astrocyte [ASK1/TLR4, TLR9] Guo et al. (59) Cancer Skin [ASK1/TGF-β, Akt, Nox4, Trx, Smad] Han et al. (8) [ASK1, ASK2] Iriyama et al. (60) Breast [ASK1/Trx] Zhao et al. (10) Prostate [ASK1/IRE1] Ma et al. (63) Brain [ASK1/Akt] Chang et al. (34) NDDs  Glauoma Retina [ASK1] Guo et al. (68)  AD PC12 cell [ASK1] Guo et al. (68)  PD SH-SY5Y cell [ASK1] Guo et al. (68)  PolyQ disease PC12 cell [ASK1/IRE1, TRAF2] Nishitoh et al. (18)  ALS NSC34 cell [ASK1/SOD1, Derlin1] Nishitoh et al. (33)  MTLE Hippocampus [ASK1] Guo et al. (68) I/R injury Myocardium [ASK1/TRAF1] Xu et al. (22) [ASK1/IRE1, JNK] Wu et al. (74) [ASK1/CaMKII, JNK] Liu et al. (75) Liver [ASK1/ARRB, TRAF6, Trx] Xu et al. (21) Brain [ASK1/CaMKII] Song et al. (78) Testis [ASK1/Trx, TXNIP] Al-Kandari et al. (79) Diabetes and its complications Islet [ASK1/Nox1] Singh et al. (81) [ASK1] Yamaguchi et al. (82) Retina [ASK1/IRE1] Zou et al. (83) Diseases . Organ/cell . Stimulation (related molecules) . Oxidative stress . ER stress . Ca2+ stimulation . NASH Hepatocyte [ASK1/TXNIP] Schuster et al. (45) Innate immunity  Bacteria Raw264.7 cell [ASK1/TLR4, Nox4, Trx, TRAF6] Matsuzawa et al. (11)  AIDS Jurkat-T cell [ASK1/Nef, Trx] Geleziunas et al. (56) [ASK1/Nef, CaMKII] Kumar et al. (36) Autoimune diseases  RA FLS [ASK1/TLR4] Philippe et al. (58)  MS Astrocyte [ASK1/TLR4, TLR9] Guo et al. (59) Cancer Skin [ASK1/TGF-β, Akt, Nox4, Trx, Smad] Han et al. (8) [ASK1, ASK2] Iriyama et al. (60) Breast [ASK1/Trx] Zhao et al. (10) Prostate [ASK1/IRE1] Ma et al. (63) Brain [ASK1/Akt] Chang et al. (34) NDDs  Glauoma Retina [ASK1] Guo et al. (68)  AD PC12 cell [ASK1] Guo et al. (68)  PD SH-SY5Y cell [ASK1] Guo et al. (68)  PolyQ disease PC12 cell [ASK1/IRE1, TRAF2] Nishitoh et al. (18)  ALS NSC34 cell [ASK1/SOD1, Derlin1] Nishitoh et al. (33)  MTLE Hippocampus [ASK1] Guo et al. (68) I/R injury Myocardium [ASK1/TRAF1] Xu et al. (22) [ASK1/IRE1, JNK] Wu et al. (74) [ASK1/CaMKII, JNK] Liu et al. (75) Liver [ASK1/ARRB, TRAF6, Trx] Xu et al. (21) Brain [ASK1/CaMKII] Song et al. (78) Testis [ASK1/Trx, TXNIP] Al-Kandari et al. (79) Diabetes and its complications Islet [ASK1/Nox1] Singh et al. (81) [ASK1] Yamaguchi et al. (82) Retina [ASK1/IRE1] Zou et al. (83) Open in new tab Table I. The relevance between ASK family and stimulation in each disease Diseases . Organ/cell . Stimulation (related molecules) . Oxidative stress . ER stress . Ca2+ stimulation . NASH Hepatocyte [ASK1/TXNIP] Schuster et al. (45) Innate immunity  Bacteria Raw264.7 cell [ASK1/TLR4, Nox4, Trx, TRAF6] Matsuzawa et al. (11)  AIDS Jurkat-T cell [ASK1/Nef, Trx] Geleziunas et al. (56) [ASK1/Nef, CaMKII] Kumar et al. (36) Autoimune diseases  RA FLS [ASK1/TLR4] Philippe et al. (58)  MS Astrocyte [ASK1/TLR4, TLR9] Guo et al. (59) Cancer Skin [ASK1/TGF-β, Akt, Nox4, Trx, Smad] Han et al. (8) [ASK1, ASK2] Iriyama et al. (60) Breast [ASK1/Trx] Zhao et al. (10) Prostate [ASK1/IRE1] Ma et al. (63) Brain [ASK1/Akt] Chang et al. (34) NDDs  Glauoma Retina [ASK1] Guo et al. (68)  AD PC12 cell [ASK1] Guo et al. (68)  PD SH-SY5Y cell [ASK1] Guo et al. (68)  PolyQ disease PC12 cell [ASK1/IRE1, TRAF2] Nishitoh et al. (18)  ALS NSC34 cell [ASK1/SOD1, Derlin1] Nishitoh et al. (33)  MTLE Hippocampus [ASK1] Guo et al. (68) I/R injury Myocardium [ASK1/TRAF1] Xu et al. (22) [ASK1/IRE1, JNK] Wu et al. (74) [ASK1/CaMKII, JNK] Liu et al. (75) Liver [ASK1/ARRB, TRAF6, Trx] Xu et al. (21) Brain [ASK1/CaMKII] Song et al. (78) Testis [ASK1/Trx, TXNIP] Al-Kandari et al. (79) Diabetes and its complications Islet [ASK1/Nox1] Singh et al. (81) [ASK1] Yamaguchi et al. (82) Retina [ASK1/IRE1] Zou et al. (83) Diseases . Organ/cell . Stimulation (related molecules) . Oxidative stress . ER stress . Ca2+ stimulation . NASH Hepatocyte [ASK1/TXNIP] Schuster et al. (45) Innate immunity  Bacteria Raw264.7 cell [ASK1/TLR4, Nox4, Trx, TRAF6] Matsuzawa et al. (11)  AIDS Jurkat-T cell [ASK1/Nef, Trx] Geleziunas et al. (56) [ASK1/Nef, CaMKII] Kumar et al. (36) Autoimune diseases  RA FLS [ASK1/TLR4] Philippe et al. (58)  MS Astrocyte [ASK1/TLR4, TLR9] Guo et al. (59) Cancer Skin [ASK1/TGF-β, Akt, Nox4, Trx, Smad] Han et al. (8) [ASK1, ASK2] Iriyama et al. (60) Breast [ASK1/Trx] Zhao et al. (10) Prostate [ASK1/IRE1] Ma et al. (63) Brain [ASK1/Akt] Chang et al. (34) NDDs  Glauoma Retina [ASK1] Guo et al. (68)  AD PC12 cell [ASK1] Guo et al. (68)  PD SH-SY5Y cell [ASK1] Guo et al. (68)  PolyQ disease PC12 cell [ASK1/IRE1, TRAF2] Nishitoh et al. (18)  ALS NSC34 cell [ASK1/SOD1, Derlin1] Nishitoh et al. (33)  MTLE Hippocampus [ASK1] Guo et al. (68) I/R injury Myocardium [ASK1/TRAF1] Xu et al. (22) [ASK1/IRE1, JNK] Wu et al. (74) [ASK1/CaMKII, JNK] Liu et al. (75) Liver [ASK1/ARRB, TRAF6, Trx] Xu et al. (21) Brain [ASK1/CaMKII] Song et al. (78) Testis [ASK1/Trx, TXNIP] Al-Kandari et al. (79) Diabetes and its complications Islet [ASK1/Nox1] Singh et al. (81) [ASK1] Yamaguchi et al. (82) Retina [ASK1/IRE1] Zou et al. (83) Open in new tab Consistently, suppression of ASK1 by other proteins negatively regulates NAFLD. Peng et al. showed that CARD6 deficiency exacerbates HFD-induced hepatic steatosis. In this context, CARD6 prevents HFD-induced hepatic steatosis via direct binding to ASK1 and inhibition of ASK1 oligomerization, which is essential for ASK1 activation (46). It has also been reported that hepatocyte-specific deletion of dual-specificity phosphatase 12 (DUSP12) exacerbates HFD-induced hepatic steatosis and inflammation. In DUSP12-knockdown L02 cells, proinflammatory cytokine production and lipogenesis are increased after palmitic acid and oleic acid treatment, which is inhibited by blocking ASK1 activity. Mechanistically, DUSP12 binds to ASK1 and suppresses its activity by promoting dephosphorylation of the critical Thr in the kinase domain after palmitic acid and oleic acid treatment in L02 cells. Altogether, DUSP12 suppresses HFD-induced hepatic steatosis and inflammation possibly via inhibition of ASK1 (47). These reports suggest that suppression of ASK1 is a therapeutic strategy for NAFLD. Regulation of ASK1 via ubiquitination is also known to occur in NAFLD. In hepatocytes, tumour necrosis factor alpha-induced protein 3 (TNFAIP3) represses ASK1 by directly binding to it and deubiquitinating it. Hepatocyte-specific TNFAIP3 ablation exacerbates NAFLD and induces phenotypes associated with NASH through ASK1 activation. Notably, polyubiquitination (K11 and K63), which is deubiquitinated by TNFAIP3, is distinct from previously reported mechanisms that promote the degradation of ASK1. This newly identified polyubiquitination is caused by a pathological level of lipid accumulation and appears to activate ASK1 (48). TRAF6 also promotes the dissociation of ASK1 from Trx via Lys6-linked polyubiquitination of ASK1 in hepatocytes, leading to ASK1 activation and promoting inflammation and fibrosis. Hepatocyte expression of TRAF6 is increased in NASH, suggesting that hepatocyte TRAF6 promotes NASH progression via activation of ASK1 (49). Supported by recent reports on the relevance between ASK1 and hepatitis, the contribution of ASK1 to NASH pathogenesis has received much attention for the development of drugs targeting ASK1, such as selonsertib. However, given that treatment with selonsertib alone was unsuccessful, concomitant use of drugs that regulate hepatitis through pathways other than ASK1 might be required for complete treatment of NASH. Innate immunity ASK1 and ASK2 are known to be involved in immune responses during viral and bacterial infections (11, 50, 51). During bacterial infection, it has been reported that ASK1 is required for TLR4-dependent induction of proinflammatory cytokines. When LPS, a component of the outer membrane of gram-negative bacteria, binds to TLR4, Nox4 binds to the cytoplasmic tail of TLR4, leading to ROS production. As described above, ROS promote ASK1 dissociation from Trx and binding to TRAF6, which activates ASK1. Furthermore, ASK1-deficient mice are resistant to LPS-induced sepsis, suggesting that ASK1 is critical in the pathogenesis of TLR4-dependent septic shock (11) (Table I). It has also been recently found that ASK1 facilitates LPS-induced preterm birth through the induction of proinflammatory cytokines (52). Camille et al. found that ASK1-deficient mice had less inflammation and lung injury in response to inhaled LPS compared to wild-type (WT) mice. Interestingly, in ASK1-deficient bone marrow-derived macrophages (BMDMs), induction of NLRP3 during LPS priming occurs at a lower rate than in WT BMDMs, indicating that ASK1 promotes the priming of the NLRP3 inflammasome (53). In mice intranasally infected with Burkholderia thailandensis, severe histopathological lesions are observed in the lungs, leading to lethal pathology presumably via excessive inflammatory responses in pulmonary lesions. In this context, NLRP3 expression is increased in BMDMs stimulated with B.thailandensis. Moreover, enhancement of NLRP3 expression after stimulation with B.thailandensis is reduced in both ASK1- and ASK2-deficient BMDMs but not in ASK1-deficient BMDMs. Consistently, simultaneous deletion of ASK1 and ASK2, but not ASK1 deletion alone, significantly extends life expectancy in B.thailandensis-infected mice, possibly via attenuation of the excessive inflammatory pathology in the lungs (54). Considering that several studies have only examined ASK1 function in the context of increased NLRP3 expression, future studies should take into account the involvement of ASK2 (44, 45, 53). Since ASK1 plays an important role in the host-side immune response, a certain bacterium has a strategy to perturb ASK1 function upon infection by delivering several effectors to prevent host immunity. For example, Edwardsiella piscicida delivers thioredoxin-like protein to the host cell, which acts as endogenous Trx and interferes with homo-oligomerization and phosphorylation of ASK1. Consequently, this system inhibits activation of p38 and ERK1/2, resulting in suppression of the innate immune response (55). As ASK1 is a MAP3K upstream of JNK and p38 but not ERK (1), it is unclear how ASK1 activates ERK1/2 during E.piscicida infection (55), which should be addressed by further research. Regardless, the fact that bacteria adopt this strategy reinforces the importance of ASK1 in the innate immune response. ASK1 is activated by infection by RNA viruses and synthetic double-stranded RNA analog polyinosinic:polycytidylic acid [poly(I:C)] through interaction with the IPS-1(adaptor protein)-TRAF complex, thereby promoting IFN-β induction and apoptosis via JNK and p38 activation. Intriguingly, in this context, ASK1 homo-oligomers and ASK1/2 hetero-oligomers function differently. ASK1 homo-oligomers induce type I IFN production and promote inflammation, whereas ASK1/2 hetero-oligomers induce apoptosis in bronchiolar epithelial cells. Given that ASK2 is specifically expressed in tissues with an abundance of epithelial cells, viruses are eliminated by apoptosis in regenerative epithelial cells; however, the virus may be removed by the immune system activated by the inflammatory response in ASK2-deficient cells (50). ASK1 has been implicated in AIDS, which is caused by infection with human immunodeficiency virus (HIV), resulting in severe systemic immunodeficiency. In AIDS, the Nef protein expressed by HIV-1 inhibits apoptosis of infected T cells by binding to ASK1 and preventing the disassociation of ASK1 from Trx (56). This antiapoptotic function is important for viral replication, leading to progression of the disease. It has been recently shown that Nef also interacts with CaMKIIδ, which causes formation of the Nef–CaMKIIδ–ASK1 heterotrimeric complex. Therefore, Nef attenuates the kinase activity of ASK1 and downstream p38 phosphorylation (36). Overall, Nef inhibits apoptosis of T cells by suppressing ASK1 activation through multiple mechanisms (Table I). Given that ASK1 regulates the immune response to RNA viruses in the lung (50), ASK1 is a potential therapeutic target against coronavirus disease 2019 (COVID-19), which has recently caused a pandemic. Further research is expected to promote the development of drugs for controlling infections via ASK family targeting. Autoimmune diseases ASK1 is also associated with autoimmune diseases, such as rheumatoid arthritis (RA) and multiple sclerosis (MS) (57–59). In RA, abnormal proliferation and invasion of fibroblasts cause inflammatory responses, leading to pathogenesis. In RA fibroblast-like synoviocytes (FLSs), ASK1 expression is induced by inflammatory cytokines, such as IL-1β and TNF. Suppression of ASK1 by a selective small-molecule inhibitor reduces FLS invasion, migration and proliferation in vitro and decreases arthritis severity in a rat collagen-induced arthritis model (57). In LPS-stimulated RA-FLS, ASK1 expression is upregulated by reduced levels of microRNA (miR)-20a, which directly targets ASK1 mRNA. Furthermore, transfection of miR-20a mimics attenuates the secretion of TLR4-dependent proinflammatory cytokines regulated by ASK1 (e.g. IL-6) (58). According to these reports, upregulation of ASK1 in FLS contributes to the pathogenesis of RA (Table I). In experimental autoimmune encephalomyelitis (EAE), a model of MS, expression of TLR4 and TLR9 is increased in activated astrocytes and microglia. The ASK1–p38 pathway is required for chemokine production in astrocytes through TLR4 and TLR9. Moreover, ASK1 deletion or oral administration of a small-molecule inhibitor of ASK1 attenuates EAE, suggesting that the TLR–ASK1–p38 pathway in glial cells is a therapeutic target of MS (59). Given that ROS are produced upon TLR4 stimulation (16), ASK1 may be activated by oxidative stress in RA and EAE (Table I). Cancer ASK1 is implicated in cancer, which is a major cause of death worldwide and has significant health consequences. There are many reports on the relationship between cancer and ASK1, and both tumour-promoting and -suppressing functions have been reported. The former is achieved by inducing the release of proinflammatory cytokines in inflammatory cells, increasing angiogenesis in oral squamous carcinoma and promoting cell proliferation in gastric cancer (60–62). The tumour-suppressing function is mediated by inducing apoptosis in various types of cancer cells (10, 34, 63). Thus, ASK1 functions quite differently depending on the organ affected by cancer (64). In the early stage of the skin tumourigenesis mouse model, ASK1 deletion but not ASK2 deletion significantly suppresses production of proinflammatory cytokines, such as TNFα and IL-6. Additionally, ASK1 deletion but not ASK2 deletion inhibits p38 activation upon H2O2 treatment in BMDMs, suggesting that ASK1 homo-oligomers promote cancer by producing proinflammatory cytokines in macrophages (Table I). Interestingly, in the same model, ASK1/2 hetero-oligomers induce apoptosis and thereby suppress cancer progression in epithelial cells (60). Nevertheless, it has been recently reported that ASK1 suppresses cancer. In the azoxymethane and dextran sodium sulfate-induced colitis-associated cancer (CAC) model, ASK1-KO mice developed more numerous and larger cancers than did WT mice. Interestingly, in this model, the ASK1–p38 pathway prevents the apoptosis of macrophages via upregulation of antiapoptotic gene expression, including cIAP1 and serpin B2. Furthermore, ASK1 deficiency impairs the bacterial killing ability of macrophages, leading to colonic inflammation. Altogether, ASK1 suppresses colonic inflammation and CAC through the maintenance of macrophages (65). Given that ASK1 promotes cancer by facilitating cytokine production from macrophages in the early stage of the skin tumorigenesis model (60), ASK1 likely promotes cancer by facilitating inflammatory responses of macrophages in the skin; in contrast, ASK1 suppresses cancer by attenuating colonic inflammation through upregulating the bacterial killing ability of macrophages in the colon. In the diethylnitrosamine-induced HCC model, ASK1-KO mice showed three times as many tumours as did WT mice. In this model, ASK1 is involved in Fas-induced hepatocyte apoptosis and the DNA damage response, which contributes to suppressing hepatic tumorigenesis (66). In some cancer cells, expression of TGF-β is increased, which often correlates with cancer malignancy. In a melanoma cell line, downregulation of TGF-β causes inactivation of Akt, which in turn increases Nox4-derived ROS production. Downregulation of TGF-β also decreases expression of Trx via lowering Smad activity. These events trigger ASK1 activation and cell death via p38 and JNK activation. Thus, it seems that TGF-β suppresses ASK1 activity in melanoma progression using a variety of strategies, suggesting that ASK1 may have an important role in cancer suppression (8) (Table I). It has been recently reported that ASK1 is associated with the underlying mechanism of some antitumour compounds that are effective in vivo (10, 64). Pristimerin, which has antitumour activity against various cancers, suppresses the activity of Trx by increasing ROS production, thereby activating the ASK1–JNK pathway, which induces apoptosis in human breast cancer cells (10). In prostate cancer, corosolic acid exerts antitumour activity by inducing apoptosis. Mechanistically, corosolic acid activates the IRE1–ASK1–JNK pathway, and IRE1 knockdown partially reduces corosolic acid-induced cytotoxicity in some prostate cancer cells (63). In human glioma cells, indomethacin has been shown to induce apoptosis through the ER stress-induced activation of ASK1–p38 apoptotic pathway (34). These reports suggest that ASK1 activation may be a therapeutic strategy for many types of cancers (Table I). Neurodegenerative diseases The increase in the number of patients with neurodegenerative diseases (NDDs) due to longer life expectancy is one of the greatest health challenges today. NDDs are characterized by neuroinflammation, progressive neural loss and associated irreversible damage (67). The typical symptoms caused by NDD are memory loss (e.g. in AD) and loss of mobility (e.g. in ALS). Many NDDs have no fundamental cure, with a significant decline in quality of life. Oxidative stress is one of the major causes of NDD, such as AD, glaucoma and Parkinson's disease, and a number of studies have reported oxidative stress-induced ASK1 activation in these diseases (68) (Table I). ASK1 is known to be activated by amyloid β (Aβ)-induced ROS and regulates neuronal cell death (9). In recent years, Meichen et al. found that ginsenoside Re, which is known to possess antioxidative properties, suppresses ROS production induced by Aβ, the ASK1–JNK pathway and apoptosis in vitro (69). In two-vessel occlusion vascular dementia (VD) model rats, oxidative stress and neuronal apoptosis are observed in the hippocampal CA1 region, which is accompanied by decreased expression of Trx and Trx reductase-1 (TrxR-1) in the hippocampus. Acupuncture treatment ameliorates cognitive impairment in VD model rats through antioxidative effects. Mechanistically, acupuncture treatment upregulates levels of Trx and TrxR-1, leading to inhibition of the ASK1–JNK pathway (70). ASK1 activation by ER stress has also been observed in NDDs. For instance, polyQ disease, ALS and mesial temporal lobe epilepsy (MTLE) have been reported to involve ER stress-induced ASK1 activation (68) (Table I). PolyQ diseases are a group of diseases in which a pathogenic protein containing an abnormally large number of glutamines is produced due to the expansion of three repeats of CAG in the coding region of a specific gene. Expansion of the polyQ sequence is the cause of various NDDs, and aggregation of denatured polyQ protein in the cytoplasm and nucleus leads to neuronal cell death. We showed that expansion of the polyQ sequence causes ER stress via proteasome dysfunction, accompanying ASK1 activation via formation of the IRE1–TRAF2–ASK1 complex, resulting in polyQ protein-induced cell death (18). We also found that a mutant SOD1 protein (SOD1mut), which is a cause of familial ALS, induces ER stress by binding to Derlin-1, a component of ER-associated degradation complex, and activates the ASK1-dependent cell death pathway. Interference of SOD1mut binding to Derlin-1 by a small-molecule inhibitor attenuates ER stress, ASK1 activation and motor neuron death (71). ASK1 deficiency also suppresses motor neuron death and extends lifespan in SOD1mut transgenic mice (33). Furthermore, K811 and K812, selective inhibitors of ASK1, suppress motor neuron death and glial activation in the lumbar spinal cord and significantly extend the lifespan of ALS model mice (72). ASK1 is activated by oxidative stress and ER stress in various NDDs and induces cell death in neurons. Since ASK1 downregulation inhibits cell death in many of these diseases, ASK1 suppression might be a common strategy to treat NDDs. I/R injury I/R injury is a disorder caused by the production of various toxic substances when blood reperfusion occurs in an ischaemic organ or tissue. It can occur in a variety of organs, and during I/R injury, oxidative stress, ER stress and the resulting cell death are induced. Although there are numerous reports of alleviation by suppressing these types of stress, effective treatment strategies have not yet been developed, and further research is needed (73). As mentioned above, these types of stress and the resulting cell death are closely related to ASK1, and indeed, a number of associations between ASK1 and I/R injuries have been reported (74–79). Activation of ASK1 in I/R injury is known to promote pathogenesis by inducing apoptosis and inflammation. Three patterns of regulation activate ASK1 in myocardial I/R injury. The first is regulation by IRE1. Recently, Ting et al. revealed a therapeutic mechanism against myocardial I/R injury based on low concentrations of LPS. In an I/R injured rat model with left anterior descending coronary artery ligation, pretreatment with low concentrations of LPS reduces activity of the IRE1–ASK1–JNK pathway. Therefore, low concentrations of LPS attenuate cardiomyocyte apoptosis and protect the myocardium from I/R injury (74). The second is Ca2+-dependent regulation. In myocardial I/R injury, expression of miR-145, which is known to inhibit expression of CAMKII, is downregulated. Then, enhanced phosphorylation of CAMKII, ASK1 and JNK is observed. Overexpression of miR-145 alleviates myocardium apoptosis by inhibiting the CaMKII–ASK1–JNK signalling pathway (75). The last is regulation by TRAF1. The protein level of TRAF1 is increased and TRAF1 exacerbates I/R injury in the myocardium via activation of the ASK1–JNK and p38 pathway (22). Considering that TRAF1 expression is increased under H2O2 stimulation, the upstream stimulus of TRAF1 regulation may be oxidative stress induced by I/R injury (Table I). The association between TRAF and ASK1 has also been reported in hepatic I/R injury. miR-214 overexpression suppresses TRAF1 expression, thereby inhibiting the TRAF1–ASK1–JNK pathway and reducing I/R injury-induced cell death in hepatocytes (76). Tollip is known to play a critical role in the progression of I/R injury in the liver. Tollip interacts with ASK1 and promotes activation of the ASK1/p38 pathway by inducing interaction between TRAF6 and ASK1 (77). On the other hand, ARRB1, a member of the β-arrestin family, interacts directly with ASK1 in hepatocytes and prevents TRAF6-mediated Lys6-linked polyubiquitination (21). This polyubiquitination promotes dissociation of ASK1 from Trx (49). Therefore, ARRB1 inhibits activation of ASK1 and reduces inflammation and cell death (21) (Table I). In hepatocytes, expression of the ARRB1 protein and miR-214 decreases during I/R injury, which may be the causes of ASK1 activation and subsequent hepatic I/R injury (21, 76). Cerebral I/R injuries that can lead to cognitive dysfunctions and memory loss have been reported to be associated with the ASK1–p38 pathway. Coimmunoprecipitation experiments showed that the hydrogen sulphide (H2S) produced by S-adenosyl-methionine/sodium hydrogen sulphide (NaHS) prevents the interaction of CaMKII with the ASK1-MKK3-p38 signalling module induced by cerebral I/R injury, thereby attenuating I/R injury in the cerebrum. This suggests that the regulation of ASK1 has a critical role in the protective effect of H2S against I/R-induced hippocampal CA1 injury in the cerebrum (78) (Table I). In testicular I/R injury, oxidative stress causes damage to spermatogenesis by inducing germ cell apoptosis. In this context, Trx expression is reduced, and TXNIP expression is increased. Consistently, the ASK1–JNK–p38 pathway is also activated. NQDI-1, an inhibitor of ASK1, prevents germ cell apoptosis via downregulation of the ASK1–JNK–p38 pathway, which suggests that ASK1 contributes to testicular I/R injury pathogenesis via apoptosis induction (79) (Table I). Altogether, ASK1 is regulated by a variety of stimuli and proteins in I/R injury, and it has been implicated in exacerbating the pathogenesis of I/R injury. As discussed below, ASK1 has also been implicated in vascular endothelial damage under oxidative stress, which is one of the symptoms seen during blood reperfusion (80). Thus, regulation of ASK1 may have a variety of effects on ameliorating the pathogenesis of I/R injury. However, further studies are indispensable to promote ASK1 as a therapeutic target. Diabetes and its complications A relationship between ASK1 and diabetes has also been reported. Misfolded toxic human islet amyloid polypeptide or amylin (hA) is known to be an important factor in type-2 diabetes mellitus. Accumulation of hA causes oxidative stress in islet β-cells via activation of Nox1, which in turn causes activation of ASK1. This activation of ASK1 correlates strongly with the progression of diabetes (81). ASK1 is also involved in type-1 diabetes in Akita mice, which harbours a mutation (Cys96Tyr) in the insulin gene and is a type-1 diabetes model mouse. Ins2C96Y induces ER stress and activates the ASK1–p38 pathway, leading to pancreatic β cell death (82). These reports indicate that ASK1 exacerbates both type-1 and type-2 diabetes (Table I). It was also found that ER stress-dependent cell death is attenuated by suppression of ASK1 in the model of diabetic retinopathy (DR), a complication of diabetes. IRE1 expression and ASK1 expression are upregulated in this model, suggesting that the IRE1–ASK1 pathway promotes DR (83). In addition, activation of ASK1 in glomerular and tubular compartments is observed in renal biopsies from patients with diabetic kidney disease (DKD). Inhibition of ASK1 by administration of GS-444217 reduces kidney inflammation and fibrosis and halts glomerular filtration rate decline in a db/db eNOS−/− mouse model of DKD, which shows pathological features similar to human DKD, such as ASK1 activation (84) (Table I). These reports suggest that activation of ASK1 in diabetes may have adverse effects on various organs. Therefore, ASK1 is a potential therapeutic target for various symptoms of diabetes, including complications. Other diseases ASK1 has been reported to be associated with endothelial cell disorders, such as atherosclerosis. Oxidized low-density lipoproteins (ox-LDL) promote the pathogenesis of atherosclerosis by inhibiting the efflux of cholesterol from endothelial cells. Moreover, ox-LDL activates the NLRP3 inflammasome and IRE1–ASK1 pathway in endothelial cells. GS-4997, an ASK1 inhibitor, partially reverses NLRP3 inflammasome activation by reducing NLRP3 and IL-1β expression (85). Similarly, Cho et al. found that in senescent human aortic endothelial cells (HAECs), ox-LDL increases ROS production and causes activation of ASK1, resulting in cell death. Thus, ASK1 appears to be involved in ox-LDL-induced vascular damage, especially in aging vessels (80). Given that diabetes promotes atherosclerosis in general, ASK1 may cause severe damage to vessels, especially in aging diabetic patients, as a complication. ASK1 also plays an important role in cardiopulmonary diseases. Oxidative stress promotes pulmonary vasculature and right ventricle (RV) remodelling in pulmonary arterial hypertension (PAH) via activation of p38. Oral administration of GS-444217 can alleviate pathological remodelling of pulmonary vasculature and RV hypertrophy, resulting in abrogation of progressive pulmonary hypertension in PAH rodent models (86). In vascular smooth muscle cells (VSMCs), ASK1 is activated by Nox1-derived ROS upon TNFα stimulation. In this context, ASK1 mediates TNFα-induced NF-κB activation, survival and proliferation of VSMCs. Interestingly, depletion of Nox1 increases expression of ASK1 in VSMCs, which may act as a compensatory mechanism, suggesting that the association between Nox1 and ASK1 may also have physiological significance in an unstimulated condition (87). Activation of ASK1 is observed in reactive gliosis. Li et al. found that phosphorylation of ASK1 and expression of glial fibrillary acidic protein (GFAP) and vimentin, markers of reactive gliosis, are enhanced in gliosis models induced by scratch injury in cultured astrocytes and spinal cord injury in rats. Exogenous Trx treatments in vitro (administration of Trx in culture medium) and in vivo (Trx injection in the subarachnoid space) suppress ASK1 activation and expression of GFAP and vimentin in these gliosis models, suggesting that ASK1 promotes reactive gliosis. It was also observed that such activation of ASK1 is accompanied by dissociation of 14-3-3 from ASK1 during scratch injury-induced astrocyte activation. This dissociation is partly inhibited by Trx treatment in vitro, leading to ASK1 inhibition. This report suggests a crosstalk of ASK1 suppressors, Trx and 14-3-3, which functions in the context of reactive gliosis (27). Tartey et al. reported that ASK1 and ASK2 are involved in PTPN6-mediated footpad inflammation using Ptpn6spin mice (mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 domain-containing phosphatase 1). ASK1 and ASK2 upregulate the p38 and NF-κB pathways and promote pathogenesis by facilitating IL-1α-driven proinflammatory signals in neutrophils. In this case, single-knockout experiments of either ASK1 or ASK2 showed that ASK1 contributes to disease progression more effectively than does ASK2, even though ASK2 also has a moderate effect on disease progression (88). Closing Remarks In this review, we present the function of the ASK family in inflammation-related diseases based on the regulatory mechanisms of ASK family. The ASK family participates in many diseases and is regulated by a variety of mechanisms, even in the same disease. This means that members of the ASK family organize various physiological responses through multiple regulation of molecular signalling. The morbidity of inflammatory diseases, including those described in this review, is increasing with aging. Therefore, suppression of ASK1 may be beneficial in the treatment of a variety of diseases, especially in elderly people. However, since ASK1 also has inhibitory effects on various cancers, treatment targeting ASK1 must be conducted carefully. ASK2 exhibits a variety of functions by interacting with ASK1. Since ASK2 has a specific distribution, unlike ubiquitous ASK1, therapies targeting ASK2 are likely to have fewer side effects than those targeting ASK1. In diseases related to ASK2-expressing organs such as the skin and lungs, ASK2 may play a pivotal role in the pathology through the regulation of ASK1 signalling pathways. In general, it is very important to elucidate the mutual relationships (regulation and difference) of ASK family kinases, including ASK3, in the future to develop effective and safe drugs targeting this family. Conflict of Interest The authors declare that there is no conflict of interest. References 1 Ichijo H. , Nishida E., Irie K., Ten Dijke P., Saitoh M., Moriguchi T., Takagi M., Matsumoto K., Miyazono K., Gotoh Y. ( 1997 ) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways . Science 275 , 90 – 94 Google Scholar Crossref Search ADS PubMed WorldCat 2 Wang X.S. , Diener K., Tan T.H., Yao Z. ( 1998 ) MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5 . Biochem. Biophys. Res. Commun . 253 , 33 – 37 Google Scholar Crossref Search ADS PubMed WorldCat 3 Kaji T. , Yoshida S., Kawai K., Fuchigami Y., Watanabe W., Kubodera H., Kishimoto T. ( 2010 ) ASK3, a novel member of the apoptosis signal-regulating kinase family, is essential for stress-induced cell death in HeLa cells . Biochem. Biophys. Res. Commun . 395 , 213 – 218 Google Scholar Crossref Search ADS PubMed WorldCat 4 Tobiume K. , Matsuzawa A., Takahashi T., Nishitoh H., Morita K.I., Takeda K., Minowa O., Miyazono K., Noda T., Ichijo H. ( 2001 ) ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis . EMBO Rep . 2 , 222 – 228 Google Scholar Crossref Search ADS PubMed WorldCat 5 Takeda K. , Shimozono R., Noguchi T., Umeda T., Morimoto Y., Naguro I., Tobiume K., Saitoh M., Matsuzawa A., Ichijo H. ( 2007 ) Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1 . J. Biol. Chem . 282 , 7522 – 7531 Google Scholar Crossref Search ADS PubMed WorldCat 6 Trevelyan S.J. , Brewster J.L., Burgess A.E., Crowther J.M., Cadell A.L., Parker B.L., Croucher D.R., Dobson R.C.J., Murphy J.M., Mace P.D. ( 2020 ) Structure-based mechanism of preferential complex formation by apoptosis signal-regulating kinases . Sci. Signal . 13 , eaay6318 Google Scholar Crossref Search ADS PubMed WorldCat 7 Naguro I. , Umeda T., Kobayashi Y., Maruyama J., Hattori K., Shimizu Y., Kataoka K., Kim-Mitsuyama S., Uchida S., Vandewalle A., Noguchi T., Nishitoh H., Matsuzawa A., Takeda K., Ichijo H. ( 2012 ) ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney . Nat. Commun . 3 , 1211 – 1285 Google Scholar Crossref Search ADS PubMed WorldCat 8 Han Z. , Kang D., Joo Y., Lee J., Oh G.H., Choi S., Ko S., Je S., Choi H.J., Song J.J. ( 2018 ) TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade . Exp. Mol. Med . 50 , 1 – 19 . Google Scholar Crossref Search ADS WorldCat 9 Kadowaki H. , Nishitoh H., Urano F., Sadamitsu C., Matsuzawa A., Takeda K., Masutani H., Yodoi J., Urano Y., Nagano T., Ichijo H. ( 2005 ) Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation . Cell Death Differ . 12 , 19 – 24 Google Scholar Crossref Search ADS PubMed WorldCat 10 Zhao Q. , Liu Y., Zhong J., Bi Y., Liu Y., Ren Z., Li X., Jia J., Yu M., Yu X. ( 2019 ) Pristimerin induces apoptosis and autophagy via activation of ROS/ASK1/JNK pathway in human breast cancer in vitro and in vivo . Cell Death Discov . 5 , 125 Google Scholar Crossref Search ADS PubMed WorldCat 11 Matsuzawa A. , Saegusa K., Noguchi T., Sadamitsu C., Nishitoh H., Nagai S., Koyasu S., Matsumoto K., Takeda K., Ichijo H. ( 2005 ) ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity . Nat. Immunol . 6 , 587 – 592 Google Scholar Crossref Search ADS PubMed WorldCat 12 Saitoh M. , Nishitoh H., Fujii M., Takeda K., Tobiume K., Sawada Y., Kawabata M., Miyazono K., Ichijo H. ( 1998 ) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1 . EMBO J . 17 , 2596 – 2606 Google Scholar Crossref Search ADS PubMed WorldCat 13 Kylarova S. , Kosek D., Petrvalska O., Psenakova K., Man P., Vecer J., Herman P., Obsilova V., Obsil T. ( 2016 ) Cysteine residues mediate high-affinity binding of thioredoxin to ASK1 . FEBS J . 283 , 3821 – 3838 Google Scholar Crossref Search ADS PubMed WorldCat 14 Gotoh Y. , Cooper J.A. ( 1998 ) Reactive oxygen species- and dimerization-induced activation of apoptosis signal-regulating kinase 1 in tumor necrosis factor-α signal transduction . J. Biol. Chem . 273 , 17477 – 17482 Google Scholar Crossref Search ADS PubMed WorldCat 15 Kim Y.S. , Morgan M.J., Choksi S., Liu Z. g. ( 2007 ) TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death . Mol. Cell 26 , 675 – 687 Google Scholar Crossref Search ADS PubMed WorldCat 16 Park H.S. , Jung H.Y., Park E.Y., Kim J., Lee W.J., Bae Y.S. ( 2004 ) Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-κB . J. Immunol . 173 , 3589 – 3593 Google Scholar Crossref Search ADS PubMed WorldCat 17 Junn E. , Han S.H., Im J.Y., Yang Y., Cho E.W., Um H.D., Kim D.K., Lee K.W., Han P.L., Rhee S.G., Choi I. ( 2000 ) Vitamin D 3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function . J. Immunol . 164 , 6287 – 6295 Google Scholar Crossref Search ADS PubMed WorldCat 18 Nishitoh H. , Matsuzawa A., Tobiume K., Saegusa K., Takeda K., Inoue K., Hori S., Kakizuka A., Ichijo H. ( 2002 ) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats . Genes Dev . 16 , 1345 – 1355 Google Scholar Crossref Search ADS PubMed WorldCat 19 Nishitoh H. , Saitoh M., Mochida Y., Takeda K., Nakano H., Rothe M., Miyazono K., Ichijo H. ( 1998 ) ASK1 is essential for JNK/SAPK activation by TRAF2 . Mol. Cell 2 , 389 – 395 Google Scholar Crossref Search ADS PubMed WorldCat 20 Fujino G. , Noguchi T., Matsuzawa A., Yamauchi S., Saitoh M., Takeda K., Ichijo H. ( 2007 ) Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1 . Mol. Cell. Biol . 27 , 8152 – 8163 Google Scholar Crossref Search ADS PubMed WorldCat 21 Xu X. , Zhang Z., Lu Y., Sun Q., Liu Y., Liu Q., Tian W., Yin Y., Yu H., Sun B. ( 2020 ) ARRB1 ameliorates liver ischaemia/reperfusion injury via antagonizing TRAF6-mediated Lysine 6-linked polyubiquitination of ASK1 in hepatocytes . J. Cell. Mol. Med . 24 , 7814 – 7828 Google Scholar Crossref Search ADS PubMed WorldCat 22 Xu W. , Zhang L., Zhang Y., Zhang K., Wu Y., Jin D. ( 2019 ) TRAF1 exacerbates myocardial ischemia reperfusion injury via ASK1–JNK/p38 signaling . J. Am. Heart Assoc . 8 , e012575 Google Scholar Crossref Search ADS PubMed WorldCat 23 Kim A.H. , Khursigara G., Sun X., Franke T.F., Chao M.V. ( 2001 ) Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 . Mol. Cell. Biol . 21 , 893 – 901 Google Scholar Crossref Search ADS PubMed WorldCat 24 Petrvalska O. , Kosek D., Kukacka Z., Tosner Z., Man P., Vecer J., Herman P., Obsilova V., Obsil T. ( 2016 ) Structural insight into the 14-3-3 protein-dependent inhibition of protein kinase ASK1 (apoptosis signal-regulating kinase 1) . J. Biol. Chem . 291 , 20753 – 20765 Google Scholar Crossref Search ADS PubMed WorldCat 25 Puckett M.C. , Goldman E.H., Cockrell L.M., Huang B., Kasinski A.L., Du Y., Wang C.-Y., Lin A., Ichijo H., Khuri F., Fu H. ( 2013 ) Integration of apoptosis signal-regulating kinase 1-mediated stress signaling with the Akt/protein kinase B-I B kinase cascade . Mol. Cell. Biol . 33 , 2252 – 2259 Google Scholar Crossref Search ADS PubMed WorldCat 26 Zhou J. , Shao Z., Kerkela R., Ichijo H., Muslin A.J., Pombo C., Force T. ( 2009 ) Serine 58 of 14-3-3ζ is a molecular switch regulating ASK1 and oxidant stress-induced cell death . Mol. Cell. Biol . 29 , 4167 – 4176 Google Scholar Crossref Search ADS PubMed WorldCat 27 Li T. , Xu R., Xia H., Hu X., Wang S., Li Y., Yan Y., Xia Y. ( 2020 ) ASK1 phosphorylation regulates astrocytic reactive gliosis in vitro and in vivo . Neurosci. Lett . 716 , 134675 Google Scholar Crossref Search ADS PubMed WorldCat 28 Cheng R. , Takeda K., Naguro I., Hatta T., Iemura S. ichiro Natsume T., Ichijo H., Hattori K. ( 2018 ) β-TrCP-dependent degradation of ASK1 suppresses the induction of the apoptotic response by oxidative stress . Biochim. Biophys. Acta 1862 , 2271 – 2280 Google Scholar Crossref Search ADS WorldCat 29 Maruyama T. , Araki T., Kawarazaki Y., Naguro I., Heynen S., Aza-Blanc P., Ronai Z., Matsuzawa A., Ichijo H. ( 2014 ) Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses . Sci. Signal . 7 , 1 – 8 Google Scholar Crossref Search ADS WorldCat 30 Nagai H. , Noguchi T., Homma K., Katagiri K., Takeda K., Matsuzawa A., Ichijo H. ( 2009 ) Ubiquitin-like sequence in ASK1 plays critical roles in the recognition and stabilization by USP9X and oxidative stress-induced cell death . Mol. Cell 36 , 805 – 818 Google Scholar Crossref Search ADS PubMed WorldCat 31 Kim I. , Xu W., Reed J.C. ( 2008 ) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities . Nat. Rev. Drug Discov . 7 , 1013 – 1030 Google Scholar Crossref Search ADS PubMed WorldCat 32 Choy K.W. , Murugan D., Mustafa M.R. ( 2018 ) Natural products targeting ER stress pathway for the treatment of cardiovascular diseases . Pharmacol. Res . 132 , 119 – 129 Google Scholar Crossref Search ADS PubMed WorldCat 33 Nishitoh H. , Kadowaki H., Nagai A., Maruyama T., Yokota T., Fukutomi H., Noguchi T., Matsuzawa A., Takeda K., Ichijo H. ( 2008 ) ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1 . Genes Dev . 22 , 1451 – 1464 Google Scholar Crossref Search ADS PubMed WorldCat 34 Chang C.Y. , Li J.R., Wu C.C., Wang J.D., Liao S.L., Chen W.Y., Wang W.Y., Chen C.J. ( 2020 ) Endoplasmic reticulum stress contributes to indomethacin-induced glioma apoptosis . Int. J. Mol. Sci . 21 , 1 – 13 Google Scholar OpenURL Placeholder Text WorldCat 35 Takeda K. , Matsuzawa A., Nishitoh H., Tobiume K., Kishida S., Ninomiya-Tsuji J., Matsumoto K., Ichijo H. ( 2004 ) Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation . EMBO Rep . 5 , 161 – 166 Google Scholar Crossref Search ADS PubMed WorldCat 36 Kumar P. , Rawat K., Sharma T., Kumari S., Saxena R., Kumar B., Baghel T., Afshan T., Siddiqi M.I., Nazir A., Ghosh J.K., Tripathi R.K. ( 2019 ) HIV-1 Nef physically associate with CAMKIIδ–ASK-1 complex to inhibit p38MAPK signalling and apoptosis in infected cells . Life Sci . 224 , 263 – 273 Google Scholar Crossref Search ADS PubMed WorldCat 37 Watanabe K. , Umeda T., Niwa K., Naguro I., Ichijo H. ( 2018 ) A PP6-ASK3 module coordinates the bidirectional cell volume regulation under osmotic stress . Cell Rep . 22 , 2809 – 2817 Google Scholar Crossref Search ADS PubMed WorldCat 38 Kleinewietfeld M. , Manzel A., Titze J., Kvakan H., Yosef N., Linker R.A., Muller D.N., Hafler D.A. ( 2013 ) Sodium chloride drives autoimmune disease by the induction of pathogenic TH 17 cells . Nature 496 , 518 – 522 Google Scholar Crossref Search ADS PubMed WorldCat 39 Kino T. , Takatori H., Manoli I., Wang Y., Tiulpakov A., Blackman M.R., Su Y.A., Chrousos G.P., DeCherney A.H., Segars J.H. ( 2009 ) Brx mediates the response of lymphocytes to osmotic stress through the activation of NFAT5 . Sci. Signal . 2 , 1 – 16 Google Scholar Crossref Search ADS WorldCat 40 Müller D.N. , Wilck N., Haase S., Kleinewietfeld M., Linker R.A. ( 2019 ) Sodium in the microenvironment regulates immune responses and tissue homeostasis . Nat. Rev. Immunol . 19 , 243 – 254 Google Scholar Crossref Search ADS PubMed WorldCat 41 Sumida Y. , Yoneda M. ( 2018 ) Current and future pharmacological therapies for NAFLD/NASH . J. Gastroenterol . 53 , 362 – 376 Google Scholar Crossref Search ADS PubMed WorldCat 42 Wang P.-X. , Ji Y.-X., Zhang X.-J., Zhao L.-P., Yan Z.-Z., Zhang P., Shen L.-J., Yang X., Fang J., Tian S., Zhu X.-Y., Gong J., Zhang X., Wei Q.-F., Wang Y., Li J., Wan L., Xie Q., She Z.-G., Wang Z., Huang Z., Li H. ( 2017 ) Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates . Nat. Med . 23 , 439 – 449 Google Scholar Crossref Search ADS PubMed WorldCat 43 Roeb E. , Geier A. ( 2019 ) Nonalcoholic steatohepatitis (NASH)—current treatment recommendations and future developments . Z Gastroenterol . 57 , 508 – 517 Google Scholar Crossref Search ADS PubMed WorldCat 44 Schuster-Gaul S. , Geisler L.J., McGeough M.D., Johnson C.D., Zagorska A., Li L., Wree A., Barry V., Mikaelian I., Jih L.J., Papouchado B.G., Budas G., Hoffman H.M., Feldstein A.E. ( 2020 ) ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model . JCI Insight 5 , e123294 Google Scholar Crossref Search ADS WorldCat 45 Schuster S. , Johnson C.D., Hennebelle M., Holtmann T., Taha A.Y., Kirpich I.A., Eguchi A., Ramsden C.E., Papouchado B.G., McClain C.J., Feldstein A.E. ( 2018 ) Oxidized linoleic acid metabolites induce liver mitochondrial dysfunction, apoptosis, and NLRP3 activation in mice . J. Lipid Res . 59 , 1597 – 1609 Google Scholar Crossref Search ADS PubMed WorldCat 46 Sun P. , Zeng Q., Cheng D., Zhang K., Zheng J., Liu Y., Yuan Y.F., Tang Y.D. ( 2018 ) Caspase recruitment domain protein 6 protects against hepatic steatosis and insulin resistance by suppressing apoptosis signal–regulating kinase 1 . Hepatology 68 , 2212 – 2229 Google Scholar Crossref Search ADS PubMed WorldCat 47 Huang Z. , Wu L.‐M., Zhang J.‐L., Sabri A., Wang S.‐J., Qin G.‐J., Guo C.‐Q., Wen H.‐T., Du B.‐B., Zhang D.‐H., Kong L.‐Y., Tian X.‐Y., Yao R., Li Y.‐P., Liang C., Li P.‐C., Wang Z., Guo J.‐Y., Li L., Dong J.‐Z., Zhang Y.‐Z. ( 2019 ) Dual specificity phosphatase 12 regulates hepatic lipid metabolism through inhibition of the lipogenesis and apoptosis signal–regulating kinase 1 pathways . Hepatology 70 , 1099 – 1118 Google Scholar Crossref Search ADS PubMed WorldCat 48 Zhang P. , Wang P.-X., Zhao L.-P., Zhang X., Ji Y.-X., Zhang X.-J., Fang C., Lu Y.-X., Yang X., Gao M.-M., Zhang Y., Tian S., Zhu X.-Y., Gong J., Ma X.-L., Li F., Wang Z., Huang Z., She Z.-G., Li H. ( 2018 ) The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis . Nat. Med . 24 , 84 – 94 Google Scholar Crossref Search ADS PubMed WorldCat 49 Wang Y. , Wen H., Fu J., Cai L., Li P.L., Zhao C.L., Dong Z.F., Ma J.P., Wang X., Tian H., Zhang Y., Liu Y., Cai J., She Z.G., Huang Z., Li W., Li H. ( 2020 ) Hepatocyte TNF receptor–associated factor 6 aggravates hepatic inflammation and fibrosis by promoting lysine 6–linked polyubiquitination of apoptosis signal-regulating kinase 1 . Hepatology 71 , 93 – 111 Google Scholar Crossref Search ADS PubMed WorldCat 50 Okazaki T. , Higuchi M., Takeda K., Iwatsuki-Horimoto K., Kiso M., Miyagishi M., Yanai H., Kato A., Yoneyama M., Fujita T., Taniguchi T., Kawaoka Y., Ichijo H., Gotoh Y. ( 2015 ) The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response . Sci. Signal . 8 , 1 – 13 Google Scholar Crossref Search ADS WorldCat 51 Okazaki T. ( 2017 ) ASK family in infection and inflammatory disease . Adv. Biol. Regul . 66 , 37 – 45 Google Scholar Crossref Search ADS PubMed WorldCat 52 Yoshikawa M. , Iriyama T., Suzuki K., Sayama S., Tsuruga T., Kumasawa K., Nagamatsu T., Homma K., Naguro I., Osuga Y., Ichijo H., Fujii T. ( 2020 ) ASK1 promotes uterine inflammation leading to pathological preterm birth . Sci. Rep . 10 , 1 – 11 Google Scholar Crossref Search ADS PubMed WorldCat 53 Immanuel C.N. , Teng B., Dong B., Gordon E.M., Kennedy J.A., Luellen C., Schwingshackl A., Cormier S.A., Fitzpatrick E.A., Waters C.M. ( 2019 ) Apoptosis signal-regulating kinase-1 promotes inflammasome priming in macrophages . Am. J. Physiol.-Lung Cell. Mol. Physiol . 316 , L418 – L427 Google Scholar Crossref Search ADS PubMed WorldCat 54 Place D.E. , Samir P., Karki R., Briard B., Vogel P., Kanneganti T.D. ( 2018 ) ASK family kinases are required for optimal NLRP3 inflammasome priming . Am. J. Pathol . 188 , 1021 – 1030 Google Scholar Crossref Search ADS PubMed WorldCat 55 Yang D. , Liu X., Xu W., Gu Z., Yang C., Zhang L., Tan J., Zheng X., Wang Z., Quan S., Zhang Y., Liu Q. ( 2019 ) The Edwardsiella piscicida thioredoxin-like protein inhibits ASK1-MAPKs signaling cascades to promote pathogenesis during infection . PLoS Pathog . 15 , e1007917 – 23 Google Scholar Crossref Search ADS PubMed WorldCat 56 Geleziunas R. , Xu W., Takeda K., Ichijo H., Greene W.C. ( 2001 ) HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell . Nature 410 , 834 – 838 Google Scholar Crossref Search ADS PubMed WorldCat 57 Nygaard G. , Di Paolo J.A., Hammaker D., Boyle D.L., Budas G., Notte G.T., Mikaelian I., Barry V., Firestein G.S. ( 2018 ) Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis . Biochem. Pharmacol . 151 , 282 – 290 Google Scholar Crossref Search ADS PubMed WorldCat 58 Philippe L. , Alsaleh G., Pichot A., Ostermann E., Zuber G., Frisch B., Sibilia J., Pfeffer S., Bahram S., Wachsmann D., Georgel P. ( 2013 ) MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes . Ann. Rheum. Dis . 72 , 1071 – 1079 Google Scholar Crossref Search ADS PubMed WorldCat 59 Guo X. , Harada C., Namekata K., Matsuzawa A., Camps M., Ji H., Swinnen D., Jorand-Lebrun C., Muzerelle M., Vitte P.A., Rückle T., Kimura A., Kohyama K., Matsumoto Y., Ichijo H., Harada T. ( 2010 ) Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway . EMBO Mol. Med . 2 , 504 – 515 Google Scholar Crossref Search ADS PubMed WorldCat 60 Iriyama T. , Takeda K., Nakamura H., Morimoto Y., Kuroiwa T., Mizukami J., Umeda T., Noguchi T., Naguro I., Nishitoh H., Saegusa K., Tobiume K., Homma T., Shimada Y., Tsuda H., Aiko S., Imoto I., Inazawa J., Chida K., Kamei Y., Kozuma S., Taketani Y., Matsuzawa A., Ichijo H. ( 2009 ) ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis . EMBO J . 28 , 843 – 853 Google Scholar Crossref Search ADS PubMed WorldCat 61 Tzeng H.E. , Tsai C.H., Chang Z.L., Su C.M., Wang S.W., Hwang W.L., Tang C.H. ( 2013 ) Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma . Biochem. Pharmacol . 85 , 531 – 540 Google Scholar Crossref Search ADS PubMed WorldCat 62 Hayakawa Y. , Hirata Y., Nakagawa H., Sakamoto K., Hikiba Y., Kinoshita H., Nakata W., Takahashi R., Tateishi K., Tada M., Akanuma M., Yoshida H., Takeda K., Ichijo H., Omata M., Maeda S., Koike K. ( 2011 ) Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer . Proc. Natl. Acad. Sci. USA 108 , 780 – 785 Google Scholar Crossref Search ADS WorldCat 63 Ma B. , Zhang H., Wang Y., Zhao A., Zhu Z., Bao X., Sun Y., Li L., Zhang Q. ( 2018 ) Corosolic acid, a natural triterpenoid, induces ER stress-dependent apoptosis in human castration resistant prostate cancer cells via activation of IRE-1/JNK, PERK/CHOP and TRIB3 . J. Exp. Clin. Cancer Res . 37 , 1 – 16 Google Scholar Crossref Search ADS PubMed WorldCat 64 Ryuno H. , Naguro I., Kamiyama M. ( 2017 ) ASK family and cancer . Adv. Biol. Regul . 66 , 72 – 84 Google Scholar Crossref Search ADS PubMed WorldCat 65 Hayakawa Y. , Hirata Y., Nakagawa H., Sakamoto K., Hikiba Y., Otsuka M., Ijichi H., Ikenoue T., Tateishi K., Akanuma M., Ogura K., Yoshida H., Ichijo H., Omata M., Maeda S. ( 2010 ) Apoptosis signal-regulating kinase 1 regulates colitis and colitis-associated tumorigenesis by the innate immune responses . Gastroenterology 138 , 1055 – 1067.e4 Google Scholar Crossref Search ADS PubMed WorldCat 66 Nakagawa H. , Hirata Y., Takeda K., Hayakawa Y., Sato T., Kinoshita H., Sakamoto K., Nakata W., Hikiba Y., Omata M., Yoshida H., Koike K., Ichijo H., Maeda S. ( 2011 ) Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated mitogen-activated protein kinase . Hepatology 54 , 185 – 195 Google Scholar Crossref Search ADS PubMed WorldCat 67 Yuste J.E. , Tarragon E., Campuzano C.M., Ros-Bernal F. ( 2015 ) Implications of glial nitric oxide in neurodegenerative diseases . Front. Cell. Neurosci . 9 , 1 – 13 Google Scholar Crossref Search ADS PubMed WorldCat 68 Guo X. , Namekata K., Kimura A., Harada C., Harada T. ( 2017 ) ASK1 in neurodegeneration . Adv. Biol. Regul . 66 , 63 – 71 Google Scholar Crossref Search ADS PubMed WorldCat 69 Liu M. , Bai X., Yu S., Zhao W., Qiao J., Liu Y., Zhao D., Wang J., Wang S. ( 2019 ) Ginsenoside Re inhibits ROS/ASK-1 dependent mitochondrial apoptosis pathway and activation of Nrf2-antioxidant response in beta-amyloid-challenged SH-SY5Y cells . Molecules 24 , 2687 . Google Scholar Crossref Search ADS WorldCat 70 Zhu W. , Wang X.R., Du S.Q., Yan C.Q., Yang N.N., Lin L.L., Shi G.X., Liu C.Z. ( 2018 ) Anti-oxidative and anti-apoptotic effects of acupuncture: role of thioredoxin-1 in the hippocampus of vascular dementia rats . Neuroscience 379 , 281 – 291 Google Scholar Crossref Search ADS PubMed WorldCat 71 Tsuburaya N. , Homma K., Higuchi T., Balia A., Yamakoshi H., Shibata N., Nakamura S., Nakagawa H., Ikeda S.I., Umezawa N., Kato N., Yokoshima S., Shibuya M., Shimonishi M., Kojima H., Okabe T., Nagano T., Naguro I., Imamura K., Inoue H., Fujisawa T., Ichijo H. ( 2018 ) A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model . Nat. Commun . 9 , 2668 Google Scholar Crossref Search ADS PubMed WorldCat 72 Fujisawa T. , Takahashi M., Tsukamoto Y., Yamaguchi N., Nakoji M., Endo M., Kodaira H., Hayashi Y., Nishitoh H., Naguro I., Homma K., Ichijo H. ( 2016 ) The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis . Hum. Mol. Genet . 25 , 245 – 253 Google Scholar Crossref Search ADS PubMed WorldCat 73 Liu D.Q. , Chen S.P., Sun J., Wang X.M., Chen N., Zhou Y.Q., Tian Y.K., Ye D.W. ( 2019 ) Berberine protects against ischemia-reperfusion injury: a review of evidence from animal models and clinical studies . Pharmacol. Res . 148 , 104385 Google Scholar Crossref Search ADS PubMed WorldCat 74 Wu T. , Jiang N., Ji Z., Shi G. ( 2019 ) The IRE1 signaling pathway is involved in the protective effect of low-dose LPS on myocardial ischemia-reperfusion injury . Life Sci . 231 , 116569 Google Scholar Crossref Search ADS PubMed WorldCat 75 Liu Z. , Tao B., Fan S., Pu Y., Xia H., Xu L. ( 2019 ) MicroRNA-145 protects against myocardial ischemia reperfusion injury via CaMKII-mediated antiapoptotic and anti-inflammatory pathways . Oxid. Med. Cell. Longev . 2019 , 1 – 14 Google Scholar OpenURL Placeholder Text WorldCat 76 Huang X. , Gao Y., Qin J., Lu S. ( 2019 ) miR-214 down-regulation promoted hypoxia/reoxygenation-induced hepatocyte apoptosis through TRAF1/ASK1/JNK pathway . Dig. Dis. Sci . 64 , 1217 – 1225 Google Scholar Crossref Search ADS PubMed WorldCat 77 Yan Z.Z. , Huang Y.P., Wang X., Wang H.P., Ren F., Tian R.F., Cheng X., Cai J., Zhang Y., Zhu X.Y., She Z.G., Zhang X.J., Huang Z., Li H. ( 2019 ) Integrated omics reveals Tollip as an regulator and therapeutic target for hepatic ischemia-reperfusion injury in mice . Hepatology 70 , 1750 – 1769 Google Scholar Crossref Search ADS PubMed WorldCat 78 Song Y.J. , Shi Y., Cui M.M., Li M., Wen X.R., Zhou X.Y., Lou H.Q., Wang Y.L., Qi D.S., Tang M., Zhang X.B. ( 2020 ) H2S attenuates injury after ischemic stroke by diminishing the assembly of CaMKII with ASK1-MKK3-p38 signaling module . Behav. Brain Res . 384 , 112520 Google Scholar Crossref Search ADS PubMed WorldCat 79 Al-Kandari N. , Fadel F., Al-Saleh F., Khashab F., Al-Maghrebi M. ( 2019 ) The thioredoxin system is regulated by the ASK-1/JNK/p38/survivin pathway during germ cell apoptosis . Molecules 24 , 1 – 18 Google Scholar Crossref Search ADS WorldCat 80 Cho K.J. , Choi S.H. ( 2019 ) ASK1 mediates apoptosis and autophagy during oxLDL-CD36 signaling in senescent endothelial cells . Oxid. Med. Cell. Longev . 2019 , 1 – 10 . Google Scholar Crossref Search ADS WorldCat 81 Singh S. , Bhowmick D.C., Pany S., Joe M., Zaghlula N., Jeremic A.M. ( 2018 ) Apoptosis signal regulating kinase-1 and NADPH oxidase mediate human amylin evoked redox stress and apoptosis in pancreatic beta-cells . Biochim. Biophys. Acta 1860 , 1721 – 1733 Google Scholar Crossref Search ADS WorldCat 82 Yamaguchi K. , Takeda K., Kadowaki H., Ueda I., Namba Y., Ouchi Y., Nishitoh H., Ichijo H. ( 2013 ) Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic ß cell exhaustion . Biochim. Biophys. Acta 1830 , 3656 – 3663 Google Scholar Crossref Search ADS PubMed WorldCat 83 Zou W. , Zou C., Zhao M., Zheng Z. ( 2019 ) ASK1 induces retinal microvascular endothelial cell apoptosis through ER stress-associated pathway . Int. J. Clin. Exp. Pathol . 12 , 1324 – 1332 Google Scholar PubMed OpenURL Placeholder Text WorldCat 84 Liles J.T. , Corkey B.K., Notte G.T., Budas G.R., Lansdon E.B., Hinojosa-Kirschenbaum F., Badal S.S., Lee M., Schultz B.E., Wise S., Pendem S., Graupe M., Castonguay L., Koch K.A., Wong M.H., Papalia G.A., French D.M., Sullivan T., Huntzicker E.G., Ma F.Y., Nikolic-Paterson D.J., Altuhaifi T., Yang H., Fogo A.B., Breckenridge D.G. ( 2018 ) ASK1 contributes to fibrosis and dysfunction in models of kidney disease . J. Clin. Invest . 128 , 4485 – 4500 Google Scholar Crossref Search ADS PubMed WorldCat 85 Hang L. , Peng Y., Xiang R., Li X., Li Z. ( 2020 ) Ox-LDL causes endothelial cell injury through ask1/nlrp3-mediated inflammasome activation via endoplasmic reticulum stress . Drug Des. Dev. Ther . 14 , 731 – 744 Google Scholar Crossref Search ADS WorldCat 86 Budas G.R. , Boehm M., Kojonazarov B., Viswanathan G., Tian X., Veeroju S., Novoyatleva T., Grimminger F., Hinojosa-Kirschenbaum F., Ghofrani H.A., Weissmann N., Seeger W., Liles J.T., Schermuly R.T. ( 2018 ) ASK1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertension . Am. J. Respir. Crit. Care Med . 197 , 373 – 385 Google Scholar Crossref Search ADS PubMed WorldCat 87 Choi H. , Stark R.J., Raja B.S., Dikalova A., Lamb F.S. ( 2019 ) Apoptosis signal-regulating kinase 1 activation by nox1-derived oxidants is required for TNFα receptor endocytosis . Am. J. Physiol.-Heart Circ. Physiol . 316 , H1528 – H1537 Google Scholar Crossref Search ADS PubMed WorldCat 88 Tartey S. , Gurung P., Dasari T.K., Burton A., Kanneganti T.D. ( 2018 ) ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis . J. Clin. Invest . 128 , 2042 – 2047 Google Scholar Crossref Search ADS PubMed WorldCat Abbreviations Abbreviations Aβ amyloid β AD Alzheimer's disease ALS amyotrophic lateral sclerosis ASK apoptosis signal-regulating kinase BMDMs bone marrow-derived macrophages CAC colitis-associated cancer CAMKII calmodulin-dependent protein kinase II COVID-19 coronavirus disease 2019 DKD diabetic kidney disease DR diabetic retinopathy EAE experimental autoimmune encephalomyelitis ER endoplasmic reticulum FLSs fibroblast-like synoviocytes GFAP glial fibrillary acidic protein HCC hepatocellular cancer HFD high-fat diet HIV human immunodeficiency virus H2S hydrogen sulphide I/R ischaemic/reperfusion MAPK mitogen-activated protein kinase MS multiple sclerosis MTLE mesial temporal lobe epilepsy NAFL nonalcoholic fatty liver NAFLD nonalcoholic fatty liver disease NaHS sodium hydrogen sulphide NASH nonalcoholic steatohepatitis NDDs neurodegenerative diseases NLRP3 NOD-like receptor protein 3 ox-LDL oxidized low-density lipoproteins PAH pulmonary arterial hypertension RA rheumatoid arthritis ROS reactive oxygen species SOD1 superoxide dismutase 1 TGF-β transforming growth factor TLR4 Toll-like receptor 4 TNF tumour necrosis factor TRAF TNF receptor-associated factor Trx thioredoxin TrxR-1 Trx reductase-1 TXNIP Trx-interacting protein UPR unfolded protein response VD vascular dementia VSMCs vascular smooth muscle cells WT wild-type. Author notes Hidenori Ichijo, Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: +81-3-5841-4859, Fax: +81-3-5841-4798, email: ichijo@mol.f.u-tokyo.ac.jp Isao Naguro, Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: +81-3-5841-4858, Fax: +81-3-5841-4798, email: nagurois@mol.f.u-tokyo.ac.jp © The Author(s) 2020. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Molecular functions of ASK family in diseases caused by stress-induced inflammation and apoptosis
JO - The Journal of Biochemistry
DO - 10.1093/jb/mvaa145
DA - 2020-12-30
UR - https://www.deepdyve.com/lp/oxford-university-press/molecular-functions-of-ask-family-in-diseases-caused-by-stress-induced-dk4f01K7ep
SP - 1
EP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -