Autophagy最新文献

{"title":"PINK1-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis.","authors":"Mariella Arcos, Lavanya Goodla, Hyeoncheol Kim, Sharina P Desai, Rui Liu, Kunlun Yin, Zhaoli Liu, David R Martin, Xiang Xue","doi":"10.1080/15548627.2024.2425594","DOIUrl":"10.1080/15548627.2024.2425594","url":null,"abstract":"<p><p>Mitophagy, the process by which cells eliminate damaged mitochondria, is mediated by PINK1 (PTEN induced kinase 1). Our recent research indicates that PINK1 functions as a tumor suppressor in colorectal cancer by regulating cellular metabolism. Interestingly, PINK1 ablation activated the NLRP3 (NLR family pyrin domain containing 3) inflammasome, releasing IL1B (interleukin 1 beta). However, inhibiting the NLRP3-IL1B signaling pathway with an IL1R (interleukin 1 receptor) antagonist or NLRP3 inhibitor did not hinder colon tumor growth after PINK1 loss. To identify druggable targets in PINK1-deficient tumors, ribonucleic acid sequencing analysis was performed on colon tumors from <i>pink1</i> knockout and wild-type mice. Gene Set Enrichment Analysis highlighted the enrichment of iron ion transmembrane transporter activity. Subsequent qualitative polymerase chain reaction and western blot analysis revealed an increase in mitochondrial iron transporters, including mitochondrial calcium uniporter, in PINK1-deficient colon tumor cells and tissues. Live-cell iron staining demonstrated elevated cellular and mitochondrial iron levels in PINK1-deficient cells. Clinically used drugs deferiprone and minocycline reduced mitochondrial iron and superoxide levels, resulting in decreased colon tumor cell growth <i>in vitro</i> and <i>in vivo</i>. Manipulating the mitochondrial iron uptake protein MCU (mitochondrial calcium uniporter) also affected cell and xenograft tumor growth. This study suggests that therapies aimed at reducing mitochondrial iron levels may effectively inhibit colon tumor growth, particularly in patients with low PINK1 expression.<b>Abbreviation</b>: ANOVA: analysis of variance; APC: adenomatous polyposis coli; cAMP: cyclic adenosine monophosphate; CDX2: caudal type homeobox 2; CGAS: cyclic GMP-AMP synthase; CRC: colorectal cancer; DNA: deoxyribonucleic acid; DFP: deferiprone; DMEM: Dulbecco's modified Eagle medium; DSS: dextran sodium sulfate; ERT2-Cre: Cre recombinase fused to a triple mutant form of the human estrogen receptor; EV: empty vector; GLB: glybenclamide/glyburide; H&E: hematoxylin and eosin; ICP-MS: inductively coupled plasma mass spectrometer; IL1B: interleukin 1 beta; kDa: kilodalton; MCU: mitochondrial calcium uniporter; MKI67: marker of proliferation Ki-67; mRNA: messenger ribonucleic acid; MTT: 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide; NLRP3: NLR family pyrin domain containing 3; OE: overexpression; PBS: phosphate-buffered saline; p-CREB: phosphorylated cAMP responsive element binding protein; PINK1: PTEN induced kinase 1; p-PRKAA/AMPK: phosphorylated protein kinase AMP-activated catalytic subunit alpha; qPCR: qualitative polymerase chain reaction; RNA-seq: ribonucleic acid sequencing; ROS: reactive oxygen species; sg: single guide; sh: short hairpin; SLC25A28: solute carrier family 25 member 28; SLC25A37/MFRN: solute carrier family 25 member 37; STING1: stimulator of interferon response cGAMP inte","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"737-753"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.","authors":"Yuyuan Zhu, Min Cao, Yancheng Tang, Yifan Liu, Haiji Wang, Jiaqi Qi, Cainian Huang, Chenghao Yan, Xu Liu, Sijia Jiang, Yufei Luo, Shaogui Wang, Bo Zhou, Haodong Xu, Ying-Ying Lu, Liming Wang","doi":"10.1080/15548627.2025.2487037","DOIUrl":"https://doi.org/10.1080/15548627.2025.2487037","url":null,"abstract":"<p><p>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 <i>PINK1</i> 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 <i>in vivo</i>. Therefore, our study provides a promising intervention strategy for neuroblastoma through the induction of pyroptosis.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal antenna senses signals from the Bone to Sustain Cognition by boosting autophagy.","authors":"Victoria Blanchet, Franck Oury, David Romeo-Guitart","doi":"10.1080/15548627.2025.2487038","DOIUrl":"https://doi.org/10.1080/15548627.2025.2487038","url":null,"abstract":"<p><p>The common occurrence of cognitive decline is one of the most significant manifestations of aging in the brain, with the hippocampus - critical for learning and memory - being one of the first regions to exhibit functional deterioration. BGLAP/OCN/osteocalcin (bone gamma-carboxyglutamate protein), a pro-youth systemic factor produced by the bone, improves age-related cognitive decline by boosting hippocampal neuronal autophagy. However, the mechanism by which hippocampal neurons detect BGLAP/OCN in the systemic milieu and adapt their downstream response was previously unknown. We determined that BGLAP/OCN modulates core primary cilia (PC) proteins, suggesting that this \"extracellular antenna\" may play a role in mediating BGLAP/OCN's anti-aging effects. Furthermore, selective downregulation of core PC proteins in the hippocampus impairs learning and memory by reducing neuronal macroautophagy/autophagy. In contrast, restoring core PC protein levels in the hippocampus of aged mice improved this phenotype and was necessary for the induction of autophagy machinery by BGLAP/OCN. Together, these findings reveal a novel mechanism through which pro-youth systemic factors, like BGLAP/OCN, can regulate neuronal autophagy and foster cognitive resilience during aging.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The alpha-coronavirus E protein inhibits the JAK-STAT pathway signaling by triggering STAT2 degradation through OPTN- and NBR1-mediated selective autophagy.","authors":"Zhao Huang, Chenyang Gao, Shaohong Huang, Sizhan Lin, WenBo Zhang, Jianyi You, Xiongnan Chen, Pei Zhou, Guihong Zhang, Lang Gong","doi":"10.1080/15548627.2025.2479671","DOIUrl":"10.1080/15548627.2025.2479671","url":null,"abstract":"<p><p>The zoonotic transmission of coronaviruses continues to pose a considerable threat to humans. Swine acute diarrhea syndrome coronavirus (SADS-CoV), a bat coronavirus related to HKU2, causes severe economic losses in the pig industry and has the potential to trigger outbreaks in humans. However, our understanding of how SADS-CoV evades the host's innate immunity remains limited, hindering effective responses to potential human outbreaks. In this study, we demonstrate that the SADS-CoV envelope protein (E) inhibits type I interferon (IFN-I) signaling by inducing the degradation of STAT2 via the macroautophagy/autophagy-lysosome pathway. Mechanistically, the E protein evades host innate immunity by promoting STAT2 degradation through autophagy, mediated by the NBR1 and OPTN receptors. Notably, ubiquitination of E protein is required for the autophagic degradation of STAT2. Additionally, lysine residue K61 of the E protein is crucial for its stable expression; however, it is not involved in its ubiquitination. In conclusion, our study reveals a novel mechanism by which the E protein disrupts IFN-I signaling by targeting STAT2 via autophagy, enhancing our understanding of SADS-CoV's immune evasion strategies and providing potential drug targets for controlling viral infections.<b>Abbreviations</b>: 3-MA: 3-methyladenine; ATG: autophagy related; BafA1: bafilomycin A₁; BSA: bovine serum albumin; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CC: coiled-coil; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; DBD: DNA-binding domain; DMEM: Dulbecco's Modified Eagle's medium; DMSO: dimethyl sulfoxide; E, Envelope. FW: four-tryptophan; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HA: hemagglutinin; hpt: hours post-treatment; IF: indirect immunofluorescence; IFNB/IFN-β: interferon beta; IgG: immunoglobulin G; ISG: IFN-stimulated genes; ISRE: interferon-stimulated response element; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PBS: phosphate-buffered saline; PRRs: pattern recognition receptors; qPCR: quantitative polymerase chain reaction; SAR: selective autophagy receptor; SQSTM1/p62: sequestosome 1; STAT: signal transduction and activator of transcription; TBS-T: Tris-buffered saline with Tween 20; TCID50: 50% tissue culture infective dose; TOLLIP: toll interacting protein; Ub: ubiquitin; UBA: C-terminal ubiquitin-associated; VSV: vesicular stomatitis virus; WB: western blotting. WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ESCRT iii-mediated lysosomal repair improve renal tubular cell injury in cisplatin-induced AKI.","authors":"Zhangyu Tian, Yiming Wu, Bin Yi, Ling Li, Yan Liu, Hao Zhang, Aimei Li","doi":"10.1080/15548627.2025.2483598","DOIUrl":"https://doi.org/10.1080/15548627.2025.2483598","url":null,"abstract":"<p><p>The chemotherapeutic agent cisplatin is widely utilized for the treatment of various solid tumors. However, its clinical utility is limited by nephrotoxicity. Although numerous studies have demonstrated the potential of enhancing macroautophagy/autophagy in alleviating cisplatin-induced acute kidney injury (AKI), the dynamics of the autophagic process during renal tubular injury remain to be elucidated. In our investigation, we observed that cisplatin treatment leads to increased expression of LC3-II, GABARAPL1, SQSTM1/p62 and NBR1 in mouse renal tubular epithelial cells and BUMPT cells. Moreover, ultrastructurally, there is extensive accumulation of autophagic vacuoles in AKI mice. These findings imply that cisplatin-induced AKI results in impaired autophagic flow within renal tubular cells. Furthermore, LGALS3 (galectin 3) was found to be enriched in lysosomes after cisplatin treatment, revealing a close association between autophagy dysfunction and impaired lysosomal membrane integrity. Given the damaging contents of lysosomes, lysosomal membrane permeabilization must be rapidly resolved. Our findings showed that ESCRT III subunit CHMP4A-mediated lysosomal membrane repair significantly ameliorates autophagic defects and protects against lysosomal damage-induced cell death in a cisplatin-induced AKI model. In conclusion, our study indicates that ESCRT III-mediated lysosomal repair can relieve cisplatin-induced cell apoptosis and restore normal autophagy function in renal tubular epithelial cells. This mechanism plays a protective role against cisplatin-induced AKI.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADSL-produced fumarate increases BECN1 dimethylation to promote autophagy and liver tumor growth.","authors":"Lei Wang, Guimei Ji, Yuran Duan, Peixiang Zheng, Zhiqiang Hu, Zheng Wang, Daqian Xu","doi":"10.1080/15548627.2025.2481125","DOIUrl":"10.1080/15548627.2025.2481125","url":null,"abstract":"<p><p>Cancer cells depend on the reprogramming of cell metabolism to constantly adapt metabolically to the tumor microenvironment. ADSL (adenylosuccinate lyase), a rate-limiting enzyme in de novo purine synthesis, is overexpressed in various cancer cells. However, whether ADSL functions in other oncogenic signaling is largely unknown. Here, our recent study shows that ADSL interacts with BECN1 (beclin 1) to regulate macroautophagy/autophagy upon lipid deprivation. Mechanistically, ADSL is phosphorylated at S140 by EIF2AK3/PERK (eukaryotic translation initiation factor 2 alpha kinase 3) in response to lipid deprivation, which enhances the association between ADSL and BECN1. ADSL-produced fumarate reduces the BECN1-associated KDM8 activity, leading to increased BECN1 K117 dimethylation. BECN1 K117 dimethylation inhibits its interaction with BCL2 to initiate autophagy. Targeting the ADSL-BECN1 axis by knock-in mutation or a cell-penetrating peptide inhibits autophagy and blunts liver tumor growth in mice. These findings broaden the physiological significance of ADSL in autophagy and liver tumor development.<b>Abbreviation</b>: α-KG: alpha-ketoglutarate; ADSL: adenylosuccinate lyase; AMP: adenosine monophosphate; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; HCC: hepatocellular carcinoma; KDM8: lysine demethylase 8; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ULK1: unc-51 like autophagy activating kinase 1; WIPI2: WD repeat domain, phosphoinositide interacting 2.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Keeping your endosymbiont under control: the enigmatic plastid membrane ATG8ylation in Apicomplexa parasites.","authors":"Sébastien Besteiro","doi":"10.1080/15548627.2025.2483445","DOIUrl":"10.1080/15548627.2025.2483445","url":null,"abstract":"<p><p>ATG8ylation of membranes has been increasingly reported over the last few years, in various configurations and across different eukaryotic models. While the unconventional conjugation of ATG8 to the outermost membrane of the plastid in apicomplexan parasites was first observed over a decade ago, it is often overlooked in literature reviews focusing on the ATG8ylation of non-autophagosomal membranes. Here, I provide a brief overview of the current knowledge on plastid ATG8ylation in these parasites and discuss a possible parallel between the evolutionary origin of this plastid and other ATG8ylation processes, such as LC3-associated phagocytosis.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-5"},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Whi2-Psr1-Psr2 complex selectively regulates TORC1 and autophagy under low leucine conditions but not nitrogen depletion.","authors":"Yitao Wang, Yang Ping, Rui Zhou, Guiqin Wang, Yu Zhang, Xueyu Yang, Mingjun Zhao, Dongsheng Liu, Madhura Kulkarni, Heather Lamb, Qingwei Niu, J Marie Hardwick, Xinchen Teng","doi":"10.1080/15548627.2025.2481014","DOIUrl":"10.1080/15548627.2025.2481014","url":null,"abstract":"<p><p>Amino acids and ammonia serve as sources of nitrogen for cell growth and were previously thought to have similar effects on yeast. Consistent with this idea, depletion of either of these two nitrogen sources inhibits the target of rapamycin complex 1 (TORC1), leading to induction of macroautophagy/autophagy and inhibition of cell growth. In this study, we show that Whi2 and the haloacid dehalogenase (HAD)-type phosphatases Psr1 and Psr2 distinguish between these two nitrogen sources in <i>Saccharomyces cerevisiae</i>, as the Whi2-Psr1-Psr2 complex inhibits TORC1 in response to low leucine but not in the absence of nitrogen. In contrast, a parallel pathway controlled by Npr2 and Npr3, components of the Seh1-associated complex inhibiting TORC1 (SEACIT), suppress TORC1 under both low leucine- and nitrogen-depletion conditions. Co-immunoprecipitations with mutants of Whi2, Psr1, Psr2 and fragments of Tor1 support the model that Whi2 recruits Psr1 and Psr2 to TORC1. In accordance, the interaction between Whi2 and Tor1 appears to increase under low leucine but decreases under nitrogen-depletion conditions. Although the targets of Psr1 and Psr2 phosphatases are not known, mutation of their active sites abolishes their inhibitory effects on TORC1. Consistent with the conservation of HAD phosphatases across species, human HAD phosphatases CTDSP1 (CTD small phosphatase 1), CTDSP2, and CTDSPL can functionally replace Psr1 and Psr2 in yeast, restoring TORC1 inhibition and autophagy activation in response to low leucine conditions.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"R406 and its structural analogs reduce SNCA/α-synuclein levels via autophagic degradation.","authors":"Chao Zhong, Xiaoge Gao, Qi Chen, Bowen Guan, Wanli Wu, Zhiqiang Ma, Mengdan Tao, Xihuan Liu, Yu Ding, Yiyan Fei, Yan Liu, Boxun Lu, Zhaoyang Li","doi":"10.1080/15548627.2025.2483886","DOIUrl":"https://doi.org/10.1080/15548627.2025.2483886","url":null,"abstract":"<p><p>The presence of neuronal Lewy bodies mainly composed of SNCA/α-synuclein aggregations is a pathological feature of Parkinson disease (PD), whereas reducing SNCA protein levels may slow the progression of this disease. We hypothesized that compounds enhancing SNCA's interaction with MAP1LC3/LC3 May increase its macroautophagic/autophagic degradation. Here, we conducted small molecule microarray (SMM)-based screening to identify such compounds and revealed that the compound R406 could decrease SNCA protein levels in an autophagy-dependent manner. We further validated the proposed mechanism, in which knockdown of essential gene <i>ATG5</i> for autophagy formation and using the autophagy inhibitor chloroquine (CQ) blocked the effect of R406. Additionally, R406 also reduced the levels of phosphorylated serine 129 of SNCA (p-S129-SNCA) in SNCA preformed fibrils (PFFs)-induced cellular models and rescued neuron degeneration.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Staphylococcus aureus</i> reprograms CASP8 (caspase 8) signaling to evade cell death and Xenophagy.","authors":"Yi-Tian Ying, Jing Yang, Hui-Wen Ye, Mei-Yi Chen, Xia Liu, Wei Chen, Jin-Xin Xu, Xun Tan","doi":"10.1080/15548627.2025.2483887","DOIUrl":"https://doi.org/10.1080/15548627.2025.2483887","url":null,"abstract":"<p><p>Regulated cell death and xenophagy constitute fundamental cellular mechanisms against invading microorganisms. <i>Staphylococcus aureus</i>, a notorious pathogen, can invade and persist within host cells for extended periods. Here, we describe a novel mechanism by which <i>S. aureus</i> subverts these host defenses through the manipulation of the CASP8 (caspase 8) signaling pathway. Upon invasion, <i>S. aureus</i> triggers the assembly of a RIPK3 (receptor interacting serine/threonine kinase 3) complex to induce CASP8 autoprocessing. However, the bacterium inhibits CUL3 (cullin 3)-dependent K63-linked ubiquitination, leading to an atypical activation of CASP8. This non-canonical activation does not initiate the CASP8-CASP3 cascade but instead suppresses RIPK3-dependent necroptosis, a regulated cell death pathway typically activated when apoptosis fails. The resulting non-apoptotic, cleaved CASP8 redirects its enzymatic activity toward cleaving SQSTM1/p62, a selective macroautophagy/autophagy receptor, thus enabling <i>S. aureus</i> to evade antimicrobial xenophagy. The results of this study suggest that <i>S. aureus</i> reprograms the CASP8 signaling pathway from inducing cell death to preserving cell survival and inhibiting xenophagy, a critical strategy that supports its stealthy replication and persistence within host cells.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}