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Pascual, Clarence; Klionsky, Daniel J.
doi: 10.1080/15548627.2025.2534072pmid: 40698512
When cells within our bodies begin to exhibit tumor-specific antigens, a specialized group of immune cells, known as immune effector cells, plays a crucial role in mounting both innate and adaptive immune responses. Cancer cells are notorious for developing strategies to hide from, suppress, and manipulate the immune system, collectively known as immune evasion. In the paper by Kam et al. the authors propose that intratumoral cell-associated, as opposed to secreted, LGALS9 (galectin 9) suppresses the activation of cytotoxic T lymphocytes in a macroautophagy/autophagy-dependent manner in nasopharyngeal carcinoma (NPC) cell lines. Abbreviations: CTL: cytotoxic T lymphocyte; NPC: nasopharyngeal carcinoma
Leng, Minghong; Yang, Fenghe; Zhao, Junhui; Xiong, Yufei; Zhou, Yiqing; Zhao, Mingyang; Jia, Shi; Liu, Limei; Zheng, Qiaoxia; Gan, Lebin; Ye, Jingjing; Zheng, Ming
doi: 10.1080/15548627.2025.2488563pmid: 40181214
Endurance exercise triggers adaptive responses especially in slow-twitch myofibers of skeletal muscles, leading to the remodeling of myofiber structure and the mitochondrial network. However, molecular mechanisms underlying these adaptive responses, with a focus on the fiber type-specific perspective, remains largely unknown. In this study we analyzed the alterations of transcriptomics and metabolomics in distinct skeletal myofibers in response to endurance exercise. We determined that genes associated with sphingolipid metabolism, namely those encoding SPHK1, S1PR1, and S1PR2, are enriched in slow-twitch but not fast-twitch myofibers from both mouse and human skeletal muscles, and found that the SPHK1-S1PR pathway is essential for adaptive responses of slow-twitch to endurance exercise. Importantly, we demonstrate that endurance exercise causes the accumulation of ceramides on stressed mitochondria, and the mitophagic degradation of ceramides results in an increase of the sphingosine-1-phosphate (S1P) level. The elevated S1P thereby facilitates mitochondrial adaptation and enhances endurance capacity via the SPHK1-S1PR1/S1PR2 axis in slow-twitch muscles. Moreover, administration of S1P improves endurance performance in muscle atrophy mice by emulating these adaptive responses. Our findings reveal that the SPHK1-S1P-S1PR1/S1PR2 axis through mitophagic degradation of ceramides in slow-twitch myofibers is the central mediator to endurance exercise and highlight a potential therapeutic target for ameliorating muscle atrophy diseases. Abbreviations CQ: chloroquine; DMD: Duchenne muscular dystrophy; EDL: extensor digitorum longus; FCCP: carbonyl cyanide p-trifluoromethoxyphenyl hydrazone; FUNDC1: FUN14 domain containing 1; GTEx: genotype-tissue expression; MYH: myosin heavy chain; mtDNA: mitochondrial DNA; PPARGC1A/PGC-1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; RG: red gastrocnemius; S1P: sphingosine-1-phosphate; S1PR: sphingosine-1-phosphate receptor; Sol: soleus; SPHK1: sphingosine kinase 1; TA: tibialis anterior; WG: white gastrocnemius
Yuan, Junhu; Ma, Jianhui; Zhang, Fanyu; Wang, Tan; Jian, Xiaxiang; Wang, Bingzhi; Li, Weiwei; Zhang, Xiaoli; Cao, Yubin; Yang, Hong; Ma, Yiming; Wang, Hongying
doi: 10.1080/15548627.2025.2489335pmid: 40205686
Autophagy plays a critical role in colitis-associated colorectal cancer (CAC). However, non-autonomous regulation of macroautophagic/autophagic flux during inflammation remains largely unexplored. Here, we show that F2rl1/Par2 deficiency (F2rl1[ΔIEC]) aggravated azoxymethane-dextran sulfate sodium-induced CAC based on tumor number and burden, promoted autophagy dysfunction characterized by SQSTM1/p62 accumulation and autophagosome-lysosome fusion inhibition in IECs, and reduced lysosomal acidification by suppressing FOXA2-induced V-ATPase ATP6V0E1 transcription. FOXA2 or ATP6V0E1 overexpression rescued autophagy impairment, reactive oxygen species accumulation, and DNA damage induced by F2RL1 deficiency in vitro and in vivo. Neutrophil-derived serine proteases suppressed FOXA2 expression, causing autophagy dysfunction. F2RL1 knockout completely blocked the effects of neutrophil proteases on FOXA2 and ATP6V0E1. The correlation between neutrophil and FOXA2-ATP6V0E1 activities was validated in ulcerative colitis and colorectal carcinoma. Therefore, F2RL1 deficiency in intestinal epithelial cells suppressed FOXA2 expression, leading to V-ATPase-mediated autophagic dysfunction and exacerbating CAC. Neutrophils may contribute to impaired autophagy and promote CAC by inactivating canonical F2RL1/PAR2 signaling via its derived proteases. F2RL1/PAR2 signaling may participate in maintaining intestinal homeostasis via autophagy. These findings provide useful insights into F2RL1/PAR2 and its cleaving serine proteases in CAC and would help in developing new therapeutic strategies for this malignancy. Abbreviations: AOM: azoxymethane; ATP6V0C: ATPase H+ transporting V0 subunit c; ATP6V0E1: ATPase H+ transporting V0 subunit e1; ATP6V1C2: ATPase H+ transporting V1 subunit C2; ATP6V1F: ATPase H+ transporting V1 subunit F; CAC: colitis-associated colorectal cancer; CRC: colorectal cancer; CTSB: cathepsin B; CTSG: cathepsin G; DEGs: differentially expressed genes; DSS: dextran sulfate sodium; FOXA2: forkhead box protein A2; F2RL1: F2R like trypsin receptor 1; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TFs: transcription factors; UC: ulcerative colitis.
Huang, Hongxin; Shi, Wendi; Yan, Huijun; Fan, Linjin; Lu, Jiajun; Long, Zhenyu; Li, Xiaowei; Li, Jiao; Wang, Jie; Liu, Linna; Qian, Jun
doi: 10.1080/15548627.2025.2492877pmid: 40223186
Ebola virus disease (EVD) caused by Zaire Ebolavirus (EBOV) infection is a major threat to public health in Africa and even worldwide, due to its extremely high mortality rate. However, there are still no effective antiviral therapies that can completely cure EVD. A comprehensive understanding of virus-host interactions would be beneficial for developing new antiviral agents. Here, we showed that CXCR4-induced macroautophagy/autophagy and was internalized to endosomes by interacting with glycoprotein (GP) on viral particles during EBOV infection; this promoted the EBOV attachment and entry, which was reduced by CXCR4 antagonist and neutralizing antibody. We also found that CXCR4 increased EBOV replication by downregulating cytotoxic GP to promote viral fitness instead of influencing the assembly of viral factory. Mechanistically, excessive EBOV GP could hijack CXCR4 sorting and transporting pathways by their interactions with HGS, one of the key components of the ESCRT machinery; subsequently GP could be carried back to the endoplasmic reticulum by CXCR4, where the E3 ubiquitin ligase RNF185 was recruited to polyubiquitinate GP in a K27- and K63-linked manner. Finally, polyubiquitinated GP was degraded in lysosomes via reticulophagy by interacting with RETREG1 (reticulophagy regulator 1), in an ATG3- and ATG5-dependent manner. Our findings revealed dual roles of CXCR4 in regulation of EBOV life cycle, either acting as an entry factor by interacting with GP on viral particles to facilitate viral entry or targeting excessive GP for reticulophagic degradation, providing new evidence that EBOV hijacked the host vesicular transportation system through efficient virus-host interactions to facilitate viral fitness. Abbreviations: Baf A1: bafilomycin A1; BDBV: Bundibugyo Ebolavirus; CHX: cycloheximide; CXCR4: C-X-C motif chemokine receptor 4; CLEC4M/DC-SIGNR: C type lectin domain family 4 member M; EBOV: Zaire Ebolavirus; EEA1: early endosome antigen 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; ESCRT: endosomal sorting complex required for transport; EVD: Ebolavirus disease; HAVCR1/TIM-1: hepatitis A virus cellular receptor 1; GP: glycoprotein; HGS: hepatocyte growth factor-regulated tyrosine kinase substrate; HIV: human immunodeficiency virus; IFL: internal fusion loop; ITCH/AIP4: itchy E3 ubiquitin protein ligase; LAMP: lysosomal associated membrane protein; LC-MS/MS: liquid chromatography mass spectrometry; PDIs: protein disulfide isomerases; RBD: receptor binding domain; RESTV: Reston Ebolavirus; RETREG1: reticulophagy regulator 1; RNF185: ring finger protein 185; SQSTM1/p62: sequestosome 1; SUDV: Sudan Ebolavirus; TAFV: Taï Forest Ebolavirus; TRIM21: tripartite motif containing 21; trVLPs: transcription- and replication-competent virus-like particles; Ub: ubiquitin.
Showing 1 to 10 of 23 Articles
doi: 10.1080/15548627.2025.2487037pmid: 40160153
Mitochondria serve as the primary source of intracellular reactive oxygen species (ROS), which play a critical role in orchestrating cell death pathways such as pyroptosis in various types of cancers. PINK1-mediated mitophagy effectively removes damaged mitochondria and reduces detrimental ROS levels, thereby promoting cell survival. However, the regulation of pyroptosis by PINK1 and ROS in neuroblastoma remains unclear. In this study, we demonstrate that inhibition or deficiency of PINK1 sensitizes ROS signaling and promotes pyroptosis in neuroblastoma cells via the BAX-caspase-GSDME signaling pathway. Specifically, inhibition of PINK1 by AC220 or knockout of PINK1 impairs mitophagy and enhances ROS production, leading to oxidation and oligomerization of TOMM20, followed by mitochondrial recruitment and activation of BAX. Activated BAX facilitates the release of CYCS (cytochrome c, somatic) from the mitochondria into the cytosol, activating CASP3 (caspase 3). Subsequently, activated CASP3 cleaves and activates GSDME, inducing pyroptosis. Furthermore, inhibition or deficiency of PINK1 potentiates the anti-tumor effects of the clinical ROS-inducing drug ethacrynic acid (EA) to inhibit neuroblastoma progression in vivo. Therefore, our study provides a promising intervention strategy for neuroblastoma through the induction of pyroptosis. Abbreviation: AC220, quizartinib; ANOVA, analysis of variance; ANXA5, annexin A5; BAX, BCL2 associated X, apoptosis regulator; BAK1, BCL2 antagonist/killer 1; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; CS, citrate synthase; CSC, cancer stem cell; CYCS, cytochrome c, somatic; DTT, dithiothreitol; DNA, deoxyribonucleic acid; EA, ethacrynic acid; Fer-1, ferroptosis inhibitor ferrostatin-1; FLT3, fms related tyrosine kinase 3; GSDMD, gasdermin D; GSDME, gasdermin E; kDa, kilodalton; LDH, lactate dehydrogenase; MFN1, mitofusin 1; MFN2, mitofusin 2; mito, mitochondria; mito-ROS, mitochondrial ROS; mtKeima, mitochondria-targeted monomeric keima-red; ml, microliter; MT-CO2, mitochondrially encoded cytochrome c oxidase II; NAC, antioxidant N-acetyl-L-cysteine; Nec-1, necroptosis inhibitor necrostatin-1; OMA1, OMA1 zinc metallopeptidase; OMM, outer mitochondrial membrane; PARP, poly(ADP-ribose) polymerase; PBS, phosphate-buffered saline; PI, propidium iodide; PINK1, PTEN induced kinase 1; PRKN/Parkin, parkin RBR E3 ubiquitin protein ligase; Q-VD, Q-VD-OPH; ROS, reactive oxygen species; sg, single guide; sh, short hairpin; STS, staurosporine; TOMM20, translocase of outer mitochondrial membrane 20; TIMM23, translocase of inner mitochondrial membrane 23; μm, micrometer; μM, micromolar.