Cell differentiation, aging, and death in spatially organized yeast communities: mechanisms and consequencesPalková, Zdena; Váchová, Libuše
doi: 10.1038/s41418-025-01485-9pmid: 40158069
Cell death is a natural part of the development of multicellular organisms and is central to their physiological and pathological states. However, the existence of regulated cell death in unicellular microorganisms, including eukaryotic and prokaryotic microbes, has been a topic of debate. One reason for the continued debate is the lack of obvious benefit from cell death in the context of a single cell. However, unicellularity is relative, as most of these microbes dwell in communities of varying complexities, often with complicated spatial organization. In these spatially organized microbial communities, such as yeast and bacterial colonies and biofilms growing on solid surfaces, cells differentiate into specialized types, and the whole community often behaves like a simple multicellular organism. As these communities develop and age, cell death appears to offer benefits to the community as a whole. This review explores the potential roles of cell death in spatially organized communities of yeasts and draws analogies to similar communities of bacteria. The natural dying processes in microbial cell communities are only partially understood and may result from suicidal death genes, (self-)sabotage (without death effectors), or from non-autonomous mechanisms driven by interactions with other differentiated cells. We focus on processes occurring during the stratification of yeast colonies, the formation of the extracellular matrix in biofilms, and discuss potential roles of cell death in shaping the organization, differentiation, and overall physiology of these microbial structures.
CD95/Fas stoichiometry in future precision medicineSica, Mauricio; Roussel, Murielle; Legembre, Patrick
doi: 10.1038/s41418-025-01493-9pmid: 40234610
CD95, also known as Fas, belongs to the tumor necrosis factor (TNF) receptor superfamily. The main biological function of this receptor is to orchestrate and control the immune response since mutations in CD95 or deregulation of its downstream signaling pathways lead to auto-immunity and inflammation. Interestingly, more than twenty years ago, pioneer studies highlighted that like TNFR1, TRAILR1 or CD40, CD95 pre-associates at the plasma membrane in a ligand-independent fashion. This self-association occurs through a domain designated pre-ligand assembly domain or PLAD. Although the disruption of this pre-association prevents CD95 signaling, no drugs targeting this region have been generated because many questions remain on the stoichiometry and conformation of this receptor. Despite more than 40.000 publications, no crystal structure of CD95 alone or in combination with its ligand, CD95L, exists. Based on other TNFR members, we herein discuss the predicted conformation of CD95 at the plasma membrane and how these putative structures might account for the induction of the cell signaling pathways.
NAT10-mediated N4-acetylcytidine modification in KLF9 mRNA promotes adipogenesisWan, Xinxing; Wang, Linghao; Khan, Md Asaduzzaman; Peng, Lin; Sun, Xiaoying; Yi, Xuan; Wang, Zhouqi; Chen, Ke
doi: 10.1038/s41418-025-01483-xpmid: 40123006
Dysfunctional adipogenesis is a major contributor of obesity. N-acetyltransferase 10 (NAT10) plays a crucial role in regulating N4-acetylcysteine (ac4C) modification in tRNA, 18SrRNA, and mRNA. As the sole “writer” in the ac4C modification process, NAT10 enhances mRNA stability and translation efficiency. There are few reports on the relationship between NAT10 and adipogenesis, as well as obesity. Our study revealed a significant upregulation of NAT10 in adipose tissues of obese individuals and high-fat diet-fed mice. Furthermore, our findings revealed that the overexpression of NAT10 promotes adipogenesis, while its silencing inhibits adipogenesis in both human adipose tissue-derived stem cells (hADSCs) and 3T3-L1 cells. These results indicate the intimate relationship between NAT10 and obesity. After silencing mouse NAT10 (mNAT10), we identified 30 genes that exhibited both hypo-ac4C modification and downregulation in their expression, utilizing a combined approach of acRIP-sequencing (acRIP-seq) and RNA-sequencing (RNA-seq). Among these genes, we validated KLF9 as a target of NAT10 through acRIP-PCR. KLF9, a pivotal transcription factor that positively regulates adipogenesis. Our findings showed that NAT10 enhances the stability of KLF9 mRNA and further activates the CEBPA/B-PPARG pathway. Furthermore, a dual-luciferase reporter assay demonstrated that NAT10 can bind to three motifs of mouse KLF9 and one motif of human KLF9. In vivo studies revealed that adipose tissue-targeted mouse AAV-NAT10 (AAV-shRNA-mNAT10) inhibits adipose tissue expansion in mice. Additionally, Remodelin, a specific NAT10 inhibitor, significantly reduced body weight, adipocyte size, and adipose tissue expansion in high-fat diet-fed mice by inhibiting KLF9 mRNA ac4C modification. These findings provide novel insights and experimental evidence of the prevention and treatment of obesity, highlighting NAT10 and its downstream targets as potential therapeutic targets.
A novel role of exostosin glycosyltransferase 2 (EXT2) in glioblastoma cell metabolism, radiosensitivity and ferroptosisMatesanz-Sánchez, Rocío; Peitzsch, Mirko; Lange, Inga; Mircetic, Jovan; Seifert, Michael; Cordes, Nils; Vehlow, Anne
doi: 10.1038/s41418-025-01503-wpmid: 40234611
Glioblastoma (GBM) employs various strategies to resist therapy, resulting in poor patient survival. A key aspect of its survival mechanisms lies in metabolic regulation, maintaining rapid growth and evading cell death. Recent studies revealed the connection between therapy resistance and ferroptosis, a lipid peroxidation-dependent cell death mechanism triggered by metabolic dysfunction. Our aim was to identify novel regulators of therapy resistance in GBM cells. We conducted a comprehensive analysis combining RNA-sequencing data from a panel of human GBM cell models and TCGA GBM patient datasets. We focused on the top-12 differentially expressed gene candidates associated with poor survival in GBM patients and performed an RNA interference-mediated screen to uncover the radiochemosensitizing potential of these molecules and their impact on metabolic activity, DNA damage, autophagy, and apoptosis. We identified exostosin glycosyltransferase 2 (EXT2), an enzyme previously described in heparan sulfate biosynthesis, as the most promising candidate. EXT2 depletion elicited reduced cell viability and proliferation as well as radiochemosensitization in various GBM cell models. Mechanistically, we explored EXT2 function by conducting untargeted and targeted metabolomics and detected that EXT2-depleted GBM cells exhibit a differential abundance of metabolites belonging to S-adenosylmethionine (SAM) metabolism. Considering these metabolic changes, we determined lipid peroxidation and found that the diminished antioxidant capacity resulting from decreased levels of metabolites in the transsulfuration pathway induces ferroptosis. Moreover, modifications of specific SAM and transsulfuration metabolism associated enzymes revealed a prosurvival and ferroptosis-reducing function when EXT2 is depleted. Collectively, our results uncover a novel role of EXT2 in GBM cell survival and response to X-ray radiation, which is controlled by modulation of ferroptosis. These findings expand our understanding of how GBM cells respond to radio(chemo)therapy and may contribute to the development of new therapeutic approaches.
GCLC desuccinylation regulated by oxidative stress protects human cancer cells from ferroptosisChen, Zixiang; Niu, Kaifeng; Li, Mengge; Deng, Yuchun; Zhang, Ji; Wei, Di; Wang, Jiaqi; Zhao, Yongliang
doi: 10.1038/s41418-025-01505-8pmid: 40188196
Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.
TTK promotes mitophagy by regulating ULK1 phosphorylation and pre-mRNA splicing to inhibit mitochondrial apoptosis in bladder cancerChen, Kang; Chen, Jinyu; Cong, Yukun; He, Qingliu; Liu, Chunyu; Chen, Jiawei; Li, Haoran; Ju, Yunjie; Chen, Liang; Song, Yarong; Xing, Yifei
doi: 10.1038/s41418-025-01492-wpmid: 40269198
Bladder cancer (BC) remains a major global health challenge, with poor prognosis and limited therapeutic options in advanced stages. TTK protein kinase (TTK), a serine/threonine kinase, has been implicated in the progression of various cancers, but its role in BC has not been fully elucidated. In this study, we show that TTK is significantly upregulated in BC tissues and cell lines, correlating with poor patient prognosis. Functional assays revealed that TTK promotes proliferation and inhibits apoptosis of BC cells. Mechanistically, TTK enhances mitophagy by directly phosphorylating ULK1 at Ser477, thereby activating the ULK1/FUNDC1-mediated mitophagy pathway. TTK knockdown disrupts mitophagy, leading to impaired clearance of damaged mitochondria, excessive accumulation of mitochondrial reactive oxygen species (mtROS), and activation of mitochondrial apoptosis. Furthermore, TTK phosphorylates SRSF3 at Ser108, preventing ULK1 exon 5 skipping and maintaining ULK1 mRNA stability. These findings show that TTK plays a key role in maintaining mitophagy in BC cells. Targeting TTK could offer a promising new approach for BC treatment by disrupting mitophagy and inducing mitochondrial apoptosis.