Autophagy最新文献

{"title":"Macrophage <i>TRIM21</i> knockout inhibits septic acute lung injury by downregulating autophagy regulator protein ubiquitination.","authors":"Fei Xie, Jia-Xin Fan, Hao Wang, Qi-Long Song, Yan-Song Xu, Qing-Su Lan, Xiu-Mei Jiang, Jie Cheng, Ya-Min Hou, Hong-Rui Yang, Xu Zhang, Qiu-Ting Zhang, Peng Wang, Long-Hao Liu, Ju-Ying Qian, Wei-Dong Qin, Ming-Xiang Zhang, Jiao-Jiao Pang, Yu-Guo Chen","doi":"10.1080/15548627.2025.2519063","DOIUrl":"https://doi.org/10.1080/15548627.2025.2519063","url":null,"abstract":"<p><p>Acute lung injury (ALI) caused by sepsis is a fatal disease characterized by an systemic inflammatory response to invading pathogens. Inducing macrophage macroautophagy/autophagy is a critical strategy to combat the inflammatory response in septic ALI. The E3 ubiquitin ligase TRIM21 plays important roles in autophagy. However, the mechanism connecting macrophage TRIM21-associated autophagy to ALI development remains unclear. Therefore, this study was aimed to investigate the role of macrophage TRIM21 in septic ALI in human and mice. TRIM21 levels were significantly increased in the macrophages of septic mice and in the peripheral blood mononuclear cells and bronchoalveolar lavage fluid of septic ALI patients relative to the controls. Intriguingly, <i>Trim21</i>-specific agonist administration exacerbated ALI and inflammatory responses in septic mice. To elucidate the role of macrophage TRIM21 in the development of septic ALI, we developed a clinically relevant macrophage <i>trim21</i>-specific knockout mouse sepsis model (<i>trim21</i>^<i>M-KO</i>). <i>trim21</i> deficiency significantly reduced mortality in septic ALI model mice by inhibiting sepsis-induced pulmonary edema and inflammatory infiltration, thereby improving the mechanical barrier properties of the alveolar mucosal epithelium and permeability of the alveolar membrane. Mechanistically, TRIM21 inhibits macrophage autophagy by enhancing the K11-linked ubiquitination of the autophagy-regulating proteins ULK1, SQSTM1/p62, BECN1/beclin1, and MAP1LC3B/LC3B and accelerating their ubiquitination-dependent proteasome degradation. This further promotes pro-inflammatory M1 macrophage polarization, aggravating the inflammation of septic lung tissue and exacerbating ALI. Collectively, our data demonstrate a novel role for macrophage TRIM21 in mediating autophagy to accelerate septic ALI. These new findings may provide a framework for potential interventions against septic ALI.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287454","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":"Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.","authors":"Huina Wang, Xiuli Yi, Di Qu, Xiangxu Wang, Hao Wang, Hengxiang Zhang, Yuqi Yang, Tianwen Gao, Weinan Guo, Chunying Li","doi":"10.1080/15548627.2025.2519066","DOIUrl":"https://doi.org/10.1080/15548627.2025.2519066","url":null,"abstract":"<p><p>Enhanced cholesterol biosynthesis is a hallmark metabolic characteristic of cancer, exerting an oncogenic role by supplying intermediate metabolites that regulate intracellular signaling pathways. The pharmacological blockade of cholesterol biosynthesis has been well documented as a promising therapeutic approach in cancer. Particularly, cholesterol biosynthesis is linked to macroautophagy/autophagy and lysosome metabolism, with the engagement of the critical autophagy regulators like MTOR to be fully activated by lysosomal cholesterol trafficking and accumulation. Previous studies have primarily focused on the role of cholesterol biosynthesis in tumor cell-intrinsic biological processes, whereas its involvement in tumor immune evasion and the underlying mechanisms related to autophagy or lysosome metabolism remain elusive. Herein, through bioinformatics analysis we discovered a negative correlation between cholesterol biosynthesis and the score of tumor-infiltrating lymphocytes in cancers. Inhibition of tumor cell cholesterol biosynthesis leads to increased infiltration and activation of CD8⁺ T cells in the tumor microenvironment, which is largely responsible for the impairment of tumor growth. Mechanistically, cholesterol biosynthesis inhibition impairs the activation of MTOR at lysosomes, thereby promoting the nuclear translocation of TFEB and downstream lysosome biosynthesis, facilitating the degradation of CD274/PD-L1 within lysosomes in tumor cells. Ultimately, the HMGCR-MTOR-LAMP1 axis that connects cholesterol, lysosome and tumor immunology, predicts poor response to immunotherapy and worse prognosis of patients with melanoma. These findings unveil an immunomodulatory role of tumorous cholesterol biosynthesis via the regulation of CD274 lysosomal degradation. Targeting cholesterol biosynthesis holds promise as a potential therapeutic strategy in cancer, particularly when combined with immune checkpoint blockade.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287523","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":"Unconventional role of ATG16L1 in the control of ATP compartmentalization during apoptosis.","authors":"Elena Terraza-Silvestre, Julia Bandera-Linero, Daniel Oña-Sánchez, Felipe X Pimentel-Muinos","doi":"10.1080/15548627.2025.2519051","DOIUrl":"https://doi.org/10.1080/15548627.2025.2519051","url":null,"abstract":"<p><p>The autophagy mediator ATG16L1 forms part of a complex that is essential for MAP1LC3/LC3 lipidation and autophagosome formation in the canonical macroautophagic/autophagic pathway. However, ATG16L1 is also involved in unconventional activities where LC3 becomes lipidated in single-membrane structures unrelated to double-membrane autophagosomes. Such atypical activities usually require the C-terminal domain of the molecule that includes 7 WD40-type repetitions (WD40 domain, WDD). The WDD acts as a docking site for upstream inducers that engage the LC3 lipidation ability of ATG16L1 in alternative membrane compartments. Given that this domain is absent in the yeast Atg16 ortholog, an intriguing idea proposes that it was added to the primitive protein during evolution to perform new physiological roles required by the appearance of multicellularity. Identification of such atypical activities and their physiological implications at the organismal level are important issues that remain to be clarified. In a recent report we describe an unconventional autophagic pathway that restrains the immunogenic potential of apoptosis, a key feature of homeostatic and developmentally regulated cell death in multicellular organisms. This signaling route emanates from apoptotic mitochondria and induces the formation of single-membrane, LC3-positive vesicles through a mechanism that requires the WDD of ATG16L1. The induced vesicles sequester ATP to inhibit the amount of ATP released from apoptotic cells and, consequently, prevent the activation of co-cultured phagocytes. Thus, this is a pathway that contributes to maintain the immunosilent nature of apoptotic cell death.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287524","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":"Correction.","authors":"","doi":"10.1080/15548627.2025.2512662","DOIUrl":"https://doi.org/10.1080/15548627.2025.2512662","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268159","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":"RETREG1-mediated reticulophagy is activated by an ATF4-CEBPG/C/EBPγ heterodimer and confers protection against lipotoxicity.","authors":"Suwei Jin, Mingzhu Yan, Yongguang Liu, Shanshan Zhang, Hongbin Song, Chenxi Cao, Yujia Li, Guibo Sun, Linhu Ye, Jianzhi Chen, Wen Han, Lingyu Li, Qi Chang","doi":"10.1080/15548627.2025.2512884","DOIUrl":"10.1080/15548627.2025.2512884","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Excessive fatty acid triggers endoplasmic reticulum (ER) stress, leading to lipotoxicity, which plays a vital role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Reticulophagy is recently identified as an integral process in maintaining ER homeostasis during ER stress. However, our knowledge of reticulophagy in lipotoxicity remains limited, and the underlying molecular mechanisms are unclear. Here we showed that mild, short-term lipotoxicity induced by palmitic acid stimulated reticulophagy &lt;i&gt;in vitro&lt;/i&gt;, mediated primarily by the selective receptor RETREG1. Knockdown of &lt;i&gt;RETREG1&lt;/i&gt; in HepG2 cells and primary hepatocytes exacerbated palmitic acid-induced cell damage and death. Having demonstrated the indispensability of ATF4 and CEBPG/C/EBPγ in transcriptional upregulation of &lt;i&gt;RETREG1&lt;/i&gt;, we found that ATF4 forms a heterodimer with CEBPG and identified their binding sites in the promoter and enhancer regions of &lt;i&gt;RETREG1&lt;/i&gt; gene. In mice with acute hepatic lipotoxicity, RETREG1-mediated reticulophagy was activated, conferring protection against liver injury, as &lt;i&gt;retreg1&lt;/i&gt; knockout mice exhibited more severe liver injury than wild-type mice. In contrast, reticulophagy initiation was defective in a high fat diet-induced mouse model of MASLD, possibly due to decreased gene expression of &lt;i&gt;Retreg1&lt;/i&gt; driven by the suppression in ATF4 and CEBPG. Our study underscores the crucial role of RETREG1-mediated reticulophagy, which is co-regulated by ATF4 and CEBPG, in response to lipotoxicity, suggesting that activation of reticulophagy may represent a strategy against MASLD.&lt;b&gt;Abbreviations:&lt;/b&gt; &lt;i&gt;ATF4&lt;/i&gt;/&lt;i&gt;Atf4&lt;/i&gt;:activating transcription factor 4;ATL3: atlastin GTPase 3; Baf A1: bafilomycin A&lt;sub&gt;1&lt;/sub&gt;;CAREs:CEBP-ATF response elements; CASP9:caspase9;&lt;i&gt;CCPG1&lt;/i&gt;/&lt;i&gt;Ccpg1&lt;/i&gt;:cell cycle progression 1; CEBPB/C/EBPβ: CCAAT enhancer bindingprotein beta; CEBPG/C/EBPγ:CCAAT/enhancerbinding protein gamma; ChIP: chromatin immunoprecipitation; Co-IP:co-immunoprecipitation; CQ: chloroquine; DDIT3: DNA damage inducibletranscript 3; EIF2A: eukaryotic translation initiation factor 2A;EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3;ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleussignaling 1; Fa/R: fasted overnight followed by refeeding with ahigh-carbohydrate, fat-free diet; FBS: fetal bovine serum; GOT1/AST:glutamic-oxaloacetic transaminase 1, soluble;GPT/ALT:glutamic pyruvic transaminase, soluble; HCD:high-carbohydrate diet; H&E: hematoxylin and eosin; HFD: high-fatdiet; &lt;i&gt;Hmox1&lt;/i&gt;:heme oxygenase 1; IHC: immunohistochemistry;KRT18/CK18: keratin 18; LDH: lactatedehydrogenase; MAP1LC3/LC3: microtubule-associated protein 1 lightchain 3; MASLD: metabolic dysfunction-associated steatotic liverdisease; MDA: malondialdehyde; ND: normalchow diet; &lt;i&gt;Nfe2l2&lt;/i&gt;:nuclear factor, erythroid derived 2, like 2; &lt;i&gt;Nqo1&lt;/i&gt;:NAD(P)H dehydrogenase, quinone 1; PA: palmitic acid;","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176369","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":"Unveiling EXOC4/SEC8: a key player in enhancing antiviral immunity by inhibiting the FBXL19-STING1-SQSTM1 signaling axis.","authors":"Lin Wang, Peili Hou, Wenqing Ma, Rong Jin, Xinxin Wei, Xingyu Li, Hongbin He, Hongmei Wang","doi":"10.1080/15548627.2025.2511077","DOIUrl":"10.1080/15548627.2025.2511077","url":null,"abstract":"<p><p>As a core aptamer for anti-DNA viral immunity, STING1 (stimulator of interferon response cGAMP interactor 1) is tightly regulated to ensure the proper functioning of the natural antiviral immune response. However, many mechanisms underlying the regulation of STING1 remain largely unknown. In this study, we identify EXOC4/SEC8 (exocyst complex component 4) as a novel positive regulator of DNA virus-triggered type I interferon signaling responses through stabilizing STING1, thereby inhibiting DNA viral replication. Mechanistically, EXOC4 suppresses K27-linked ubiquitination of STING1 at K338, K347, and K370 catalyzed by the E3 ligase FBXL19 (F-box and leucine rich repeat protein 19), thereby preventing ubiquitinated-STING1 from recognition by SQSTM1 (sequestosome 1) for autophagic degradation. Importantly, mice conditionally knocked out for <i>Exoc4/Sec8</i> are more susceptible to herpes simplex virus type 1 (HSV-1) infection and exhibit more severe lung pathology compared to control mice. This further confirms the important role of EXOC4/SEC8 in antiviral natural immunity. Taken together, our study reveals the importance of EXOC4/SEC8 in promoting STING1-centered antiviral natural immunity and highlights its potential as an anti-DNA viral therapeutic target.<b>Abbreviations</b>: ACTB/β-actin: actin beta; BMDMs: bone marrow-derived macrophages; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; cGAMP: cyclic GMP-AMP; CQ: chloroquine; ER: endoplasmic reticulum; EXOC4/SEC8: exocyst complex component 4; CGAS: cyclic GMP-AMP synthase; HAdV-4: human adenovirus type 4; HSV-1: herpes simplex virus type 1; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFIT2: interferon induced protein with tetratricopeptide repeats 2; IFNB1: interferon beta 1; IRF3: interferon regulatory factor 3; IFN-I: type I interferon; ISGs: IFN-stimulated genes; ISRE: IFN-stimulated response element; MG132/Z-LLL-CHO: carbobenzoxy-Leu-Leu-leucinal; MOI: multiplicity of infection; MST: microscale thermophoresis; PMs: peritoneal macrophages; Poly(dA:dT): polydeoxyadenylic-thymidylic acid; qPCR: quantitative real-time PCR; shRNAs: short hairpin RNAs; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TCID₅₀: 50% tissue culture infectious dose; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144847","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":"Pseudorabies virus gM protein and herpesvirus homologs block selective autophagy to enhance viral replication.","authors":"Qiongqiong Zhou, Deshi Shi, Yan-Dong Tang, Longfeng Zhang, Hongyang Liu, Guangqiang Ye, Zhaoxia Zhang, Boli Hu, Li Huang, Changjiang Weng","doi":"10.1080/15548627.2025.2511584","DOIUrl":"https://doi.org/10.1080/15548627.2025.2511584","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a biological process that sequesters and degrades cytoplasmic material, damaged organelles, and infectious pathogens in eukaryotic cells via lysosomes. Autophagy is involved in different phases of the viral life cycle and regulates viral replication. Here, we demonstrated that pseudorabies virus (PRV) infection induced incomplete autophagy, and blocking the autophagosome-lysosome fusion facilitated PRV replication. Mechanistically, PRV late envelope glycoprotein M (gM) triggered SQSTM1/p62-dependent selective autophagy. Meanwhile, gM protein was found to inhibit the fusion between autophagosomes and lysosomes by activating CASP3 (caspase 3) to degrade SNAP29, resulting in increased viral replication. Interestingly, we confirmed that the gM homologs from several herpesviruses (herpes simplex virus-1, human cytomegalovirus, equine herpesvirus-1, and varicella-zoster virus) shared the same function of activating CASP3 and inhibiting autophagic flux. Deletion of the <i>CASP3</i> gene led to an intact autophagic pathway and the increased formation of autolysosomes. Collectively, our results illustrated that blockage of autophagosome-lysosome fusion mediated by PRV gM and its homologs in other herpesviruses protected viral proteins from host autophagic signaling, thus facilitating herpesvirus replication.<b>Abbreviations</b>: 3-MA: 3-methyladenine; Baf A1: bafilomycin A1; CASP3: caspase 3; cl-CASP3: cleaved-CASP3; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DMSO: dimethyl sulfoxide; EHV-1: equine herpesvirus 1; gM: glycoprotein M; HCMV: human cytomegalovirus; HSV-1: herpes simplex virus 1; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; OD: optical density; PCR: polymerase chain reaction; PFU: plaque forming units; PRV: pseudorabies virus; Rap: rapamycin; SNAP29; synaptosome associated protein 29; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TCID: 50% tissue culture infectious doses; UBA: ubiquitin-binding domain; VAMP8: vesicle associated membrane protein 8; µm, micrometer; VZV: varicella-zoster virus; WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217810","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":"Corrigendum.","authors":"","doi":"10.1080/15548627.2025.2508380","DOIUrl":"https://doi.org/10.1080/15548627.2025.2508380","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210471","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>Salmonella</i> Typhimurium persistently infects host via its effector SseJ-induced PHB2-mediated mitophagy.","authors":"Dage Sun, Hongchao Gou, Yu Zhang, Jiayi Li, Changzhi Dai, Haiyan Shen, Kaifeng Chen, Yu Wang, Peng Pan, Ting Zhu, Chenggang Xu, Tongling Shan, Ming Liao, Jianmin Zhang","doi":"10.1080/15548627.2025.2462511","DOIUrl":"10.1080/15548627.2025.2462511","url":null,"abstract":"<p><p>Despite decades of research on effective methods to resist <i>Salmonella enterica</i> serovar Typhimurium (<i>S</i>. Typhimurium) pathogenicity, the mechanisms of <i>S</i>. Typhimurium-host interactions have not been fully determined. <i>S</i>. Typhimurium is characterized as an important zoonosis in public health worldwide because of its endemicity, high morbidity, and difficulty in applying control and prevention measures. Herein, we introduce a novel bacterial factor, secretion system effector J (SseJ), and its interactive host protein, PHB2 (prohibitin 2). We explored whether SseJ affected <i>S</i>. Typhimurium replication and survival in the host. <i>S</i>. Typhimurium infection caused severe mitochondrial damage and mitophagy, which facilitated <i>S</i>. Typhimurium proliferation in cells. <i>S</i>. Typhimurium SseJ activated the PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase)-autophagosome-dependent mitophagy pathway, aided by the mitophagy receptor PHB2, for bacterial survival and persistent infection. Moreover, suppression of mitophagy alleviated the pathogenicity of <i>S</i>. Typhimurium. In conclusion, <i>S</i>. Typhimurium infection could be antagonized by targeting the SseJ-PHB2-mediated host mitochondrial autophagy pathway.<b>Abbreviation</b>: ACTB: actin beta; BafA1: bafilomycin A₁; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; co-IP: co-immunoprecipitation; CFU: colony-forming units; COX4/COXIV: cytochrome c oxidase subunit 4; CQ: chloroquine; hpi: h post-bacterial infection; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1:mitophagy inhibitor mitochondrial division inhibitor 1; MFN2: mitofusin 2; MG132: z-leu-leu-leucinal; MOI: multiplicity of infection; mtDNA: mitochondrial DNA; PBS: phosphate-buffered saline; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; qPCR: quantitative real-time reverse transcription PCR; Roc-A: Rocaglamide A; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; SCVs: <i>Salmonell</i>a-containing vacuoles; siRNA: small interfering RNA; SPI-2: <i>Salmonella</i> pathogenicity island 2; SseJ: secretion system effector J; <i>S</i>. Typhimurium: <i>Salmonella enterica</i> serovar Typhimurium; <i>S</i>.T-<i>ΔSseJ</i>: SseJ gene-deleted <i>Salmonella</i> Typhimurium strains; <i>S</i>.T-<i>CΔSseJ</i>: SseJ-complemented <i>Salmonella</i> Typhimurium strains; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1228-1244"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium release from damaged lysosomes triggers stress granule formation for cell survival.","authors":"Aravinth Kumar Jayabalan, Aanuoluwakiitan Ayeni, Jingyue Jia","doi":"10.1080/15548627.2025.2468910","DOIUrl":"10.1080/15548627.2025.2468910","url":null,"abstract":"<p><p>Lysosomes are essential membrane-bound organelles that integrate intracellular needs and external signals through multiple functions, including autophagy-mediated degradation and MTORC1 signaling. The integrity of the lysosomal membrane is therefore crucial for maintaining cellular homeostasis. Various endogenous and exogenous factors can damage lysosomes, contributing to diseases such as infections, cancer, and neurodegeneration. In response, cells mount defensive mechanisms to cope with such stress, including the formation of stress granules (SGs)-membrane-less organelles composed of RNAs and protein complexes. While SGs have emerged as key players in repairing damaged lysosomes, how lysosomal damage triggers their formation and influences cell fate remains unclear. Here we report that the calcium signal from damaged lysosomes mediates SG formation and protects cells from lysosomal damage-induced cell death. Mechanistically, calcium leakage from damaged lysosomes signals the recruitment of calcium-activating protein PDCD6IP/ALIX and its partner PDCD6/ALG2. This complex regulates protein kinase EIF2AK2/PKR and its activator PRKRA/PACT, which phosphorylates translation initiator factor EIF2S1, stalling global translation initiation. This translation arrest leads to the accumulation of inactive messenger ribonucleoprotein complexes (mRNPs), resulting in SG formation. Cells deficient in SG formation show increased cell death when exposed to lysosomal damage from disease-associated factors including SARS-CoV-2^ORF3a, adenovirus, malarial pigment, proteopathic MAPT/tau, or environmental hazards. Collectively, this study reveals how damaged lysosomes signal through calcium to trigger SG assembly, promoting cell survival. This establishes a novel link between membrane-bound and membrane-less organelles, with implications for diseases involving lysosome and SG dysfunction.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1390-1392"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}