Autophagy最新文献

{"title":"A new agent in the matrix: PINK1's expanded role in mitochondrial surveillance and regulation.","authors":"Ian Collinson, Robin A Corey, Adam G Grieve","doi":"10.1080/15548627.2026.2726091","DOIUrl":"10.1080/15548627.2026.2726091","url":null,"abstract":"<p><p>The identification of pathogenic autosomal recessive mutations in the gene encoding the PINK1 kinase provided early evidence linking mitochondrial dysfunction to neurodegeneration - in this case Parkinson's Disease. PINK1 has since become synonymous with mitophagy, with the prevailing model proposing two alternative fates. The first being partial import - inner-membrane penetration of its transmembrane domain (TMD) followed by PARL-mediated cleavage and degradation. This happens in healthy mitochondria with a high membrane potential (ΔΨ) across the inner-membrane - required for passage of proteins into or across the inner-membrane. The second being surface stabilisation, Parkin activation and initiation of mitophagy upon membrane depolarisation. But what if PINK1 acts in active mitochondria as well? Our recent work identifies a third fate - matrix entry. The findings expand the biology of PINK1 beyond mitochondrial surveillance for quality control alone. They suggest an additional mitophagy-independent regulatory role within the matrix, which turns out to be governed by the unusual properties of its TMD for the conferral of a decisive conformational switch.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":14.3,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148842450","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":"Heat shock-induced autophagy has cargo selectivity in <i>Saccharomyces cerevisiae</i>.","authors":"Dimitra Dialynaki, Yuxiang Huang, Daniel J Klionsky","doi":"10.1080/15548627.2026.2724473","DOIUrl":"10.1080/15548627.2026.2724473","url":null,"abstract":"<p><p>Mechanisms aimed at recovering from heat-induced damage are closely associated with the organism's ability to survive extreme temperature exposure. In such a scenario, we show that autophagy, as a cytoprotective mechanism, ensures recovery and viability after induced heat stress in <i>Saccharomyces cerevisiae</i>. Our findings indicate that heat shock triggers the targeted degradation of ubiquitinated protein aggregates, mediated by the macroaggrephagy receptor Cue5. Moreover, heat stress induces the turnover of the aggrephagy receptor Cct2 and the polyglutamine repeats of the HTT (huntingtin) protein (polyQ-HTT). Notably, even though Cct2 and polyQ-HTT degradation is vacuole-dependent, it is mediated autonomously of canonical autophagy pathways. Collectively, this study demonstrates a novel role of autophagy in maintaining protein homeostasis after heat stress in yeast and provides insights into the potential medical applications of heat treatment.<b>Abbreviations</b>: Atg1: AuTophaGy related 1; Atg7: AuTophaGy related 7; Atg8: AuTophaGy related 8; Atg13: AuTophaGy related 13; Atg15: AuTophaGy related 15; Cct2: Chaperonin Containing TCP-1 2; CMA: chaperone-mediated autophagy; Cue5: Coupling of Ubiquitin conjugation to ER degradation 5; GFP: green fluorescent protein; HS: heat shock/stress; HTT: huntingtin; Pep4: carboxyPEPtidase Y-deficient 4; polyQ: polyglutamine; RFP: red fluorescent protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-11"},"PeriodicalIF":14.3,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835502","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":"10.1080/15548627.2026.2728210","DOIUrl":"https://doi.org/10.1080/15548627.2026.2728210","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1"},"PeriodicalIF":14.3,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148876896","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":"Liver-originated selective autophagy of BTD by alectinib underlies concurrent hepatotoxicity and dermatotoxicity.","authors":"Xiangliang Huang, Shaoyin Zhang, Yuan Mu, Yourong Zhou, Xueqin Chen, Bing Xia, Zhifei Xu, Xiaochun Yang, Bo Yang, Qiaojun He, Hao Yan, Peihua Luo","doi":"10.1080/15548627.2026.2672162","DOIUrl":"10.1080/15548627.2026.2672162","url":null,"abstract":"<p><p>Alectinib serves as an indispensable treatment for ALK (ALK receptor tyrosine kinase)-positive non-small-cell lung cancer (NSCLC), yet its hepatotoxicity and dermatotoxicity pose significant clinical concerns due to poorly understood mechanisms. This study demonstrated that alectinib-induced dermatotoxicity was secondary to hepatotoxicity. Integrated multi-omics analysis revealed that alectinib triggered excessive macroautophagic/autophagic degradation of hepatic BTD (biotinidase), causing systemic biotin deficiency that drove both hepatocyte apoptosis and skin barrier dysfunction. Mechanistically, we discovered increased phosphorylation of NBR1 at Ser656, a previously uncharacterized site, which conferred protein stability and contributed to selective BTD degradation. Importantly, exogenous biotin supplementation concurrently mitigated alectinib-induced hepatotoxicity and dermatotoxicity, providing a strategy for safer clinical application. These results uncovered a novel paradigm in drug-induced multi-organ toxicity, in which dysregulated inter-organ crosstalk served as a central mechanistic element.<b>Abbreviations</b>: AAV: adeno-associated virus; ALK: ALK receptor tyrosine kinase; BTD: biotinidase; c-CASP3: cleaved CASP3; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DHE: dihydroethidium; ELISA: enzyme-linked immunosorbent assay; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic--pyruvic transaminase; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HPH: human primary hepatocyte; HRP: horseradish peroxidase; KEGG: Kyoto Encyclopedia of Genes and Genomes; KRT1: keratin 1; KRT5: keratin 5; KRT10: keratin 10; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPHs: mouse primary hepatocytes; MSEA: metabolite set enrichment analysis; OCR: oxygen consumption rates; PBS: phosphate-buffered saline; PCA: principal component analysis; PLS-DA: partial least squares discriminant analysis; PTMs: post-translational modifications; ROS: reactive oxygen species; RSD: relative standard deviation; SD: standard deviation; SQSTM1/p62: sequestosome 1; SRB: sulforhodamine B; TBIL: total bilirubin; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2424-2449"},"PeriodicalIF":14.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13502023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147870912","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":"<i>S</i>-palmitoylation of ATG4B facilitates the deconjugation of LC3-II to promote autophagy.","authors":"Jiaxin Wang, Huini Zeng, Wenyan Wu, Jia Yao, Yu Wang, Jiayue Han, Weiyin Zou, Shangze Li, Aimin Yang","doi":"10.1080/15548627.2026.2672699","DOIUrl":"10.1080/15548627.2026.2672699","url":null,"abstract":"<p><p>Macroautophagy/autophagy plays a critical role in maintaining cellular homeostasis. A defining characteristic of autophagy is the formation of the autophagosomes, which is regulated by a series of ATG (autophagy related) proteins. ATG4B serves as a pivotal protein responsible for the cleavage of the precursor form of MAP1LC3/LC3 and the deconjugation of LC3-II, which is a prerequisite for the formation and expansion of phagophores, the precursors to autophagosomes. In the present study, we demonstrated that ATG4B undergoes <i>S</i>-palmitoylation, in which palmitic acid is attached to the side chain of a cysteine residue. <i>S</i>-palmitoylation of ATG4B is catalyzed by ZDHHC9 (zDHHC palmitoyltransferase 9), and reversed by ABHD17B (abhydrolase domain containing 17B, depalmitoylase). Interestingly, <i>S</i>-palmitoylation of ATG4B at Cys89 is crucial for LC3-II deconjugation <i>in vitro</i> and <i>in vivo</i>, but not for proLC3 cleavage. In conclusion, our study reveals a crucial role of ATG4B <i>S</i>-palmitoylation in the deconjugation of LC3-II in autophagy.<b>Abbreviations</b>: ABE: acyl-biotin exchange assay; ABHD17A: abhydrolase domain containing17A, depalmitoylase; Alk-C16: alkynyl palmitic acid; Alk-C18: alkynyl stearic acid; ATG: autophagy related; BafA₁: bafilomycin A₁; 2-BP: 2-bromopalmitate; co-IP: co-immunoprecipitation; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; HAM: hydroxylamine; H₂O₂: hydrogen peroxide; KO: knockout; LYPLA1/APT1: lysophospholipase 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NP-40: Nonidet P-40; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; proLC3: the precursor form of LC3; PTM: posttranslational modification; SDS: sodium dodecyl sulfate; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; WIPI2B: WD repeat domain, phosphoinositide interacting 2B; WT: wild-type; ZDHHC: zDHHC palmitoyltransferase.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2393-2404"},"PeriodicalIF":14.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147870908","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":"RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.","authors":"Waka Kojima, Ryu Endo, Kei Okatsu, Hiroki Kinefuchi, Tomoko Tokita, Reika Kikuchi, Noriyuki Matsuda, Shuya Fukai, Koji Yamano","doi":"10.1080/15548627.2026.2728346","DOIUrl":"https://doi.org/10.1080/15548627.2026.2728346","url":null,"abstract":"<p><p>Damaged mitochondria are selectively eliminated through mitophagy, a critical quality control process. A kinase PINK1 and an E3 ubiquitin ligase PRKN/Parkin, both of which are mutated in familial Parkinson disease, amplify ubiquitin signals on the damaged mitochondria. The autophagy receptor OPTN plays a pivotal role in mitophagy by bridging ubiquitinated mitochondria with autophagy components. Although OPTN is known to recruit ATG9A-positive vesicles to facilitate mitophagy progression, the precise molecular mechanisms governing this recruitment remain poorly understood. In this study, we identify the small RAB GTPases RAB1A and RAB1B as direct binding partners of the OPTN leucine zipper (LZ) domain. We demonstrate that RAB1A/1B is required for the recruitment of ATG9A vesicles to mitochondria during the initial stages of mitophagy. Knockdown of RAB1A and RAB1B significantly impaired the assembly of OPTN at phagophore formation sites, leading to a profound inhibition of mitophagy progression. Mechanistically, we found that RAB1A/1B associate with ATG9A-positive vesicles via their C-terminal prenylation, thereby tethering these vesicles to the OPTN-bound mitochondria. Our findings establish a novel OPTN-RAB1-ATG9A axis that drives the <i>de novo</i> synthesis of phagophore membranes in close proximity to damaged mitochondria. This work clarifies how selective autophagy receptors spatially coordinate membrane trafficking to ensure the efficient clearance of dysfunctional organelles.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148876931","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 autophagic and non-autophagic functions of the <i>S. cerevisiae</i> PROPPIN Hsv2.","authors":"Matthew F Taylor, Jan Foerster, Florian Kramer, Noreen Strubel, Michael Thumm","doi":"10.1080/15548627.2026.2671338","DOIUrl":"10.1080/15548627.2026.2671338","url":null,"abstract":"<p><p>Autophagosome formation depends on PtdIns3P, its presence is deciphered by PROPPINs, a family of β-propellers, which in yeast consists of Atg18, Atg21 and Hsv2 and in mammals of WIPI1, WIPI2, WDR45B/WIPI3 and WDR45/WIPI4. While Atg18 is required for scaffolding the Atg2-Atg9 complex, which mediates non-vesicular membrane transport to the phagophore, Atg21 organizes the Atg8 lipidation machinery. Atg18 further acts as part of a retromer complex in vacuole fragmentation. So far, the function of Hsv2 remained elusive. Here we show that Hsv2 is required for autophagy of large cargos such as the fatty acid synthase complex (FAS) and ribosomes. We further found that Hsv2 interacts with the key retromer component Vps35 and mediates vacuole fission cooperatively with Atg18. Interestingly, the residues for interaction of Hsv2 with Atg2 and Vps35 are distinct from those of Atg18. Hsv2 is known to affect the biogenesis of the spore wall, which prompted us to include diploid cells in our analyses. We found that Hsv2 interacts with the SNARE Pep12, and that Pep12 mislocalized to the vacuole in diploid but not haploid <i>hsv2∆</i> cells. This suggests a role of Hsv2 in protein sorting in diploid cells. The loop 6C/D of PROPPINs partially inserts into membranes causing their bending. We found that the membrane bending activity of Hsv2 is required for vacuole fragmentation and sorting in diploids but not for its autophagic function. Mutations in WDR45/WIPI4, the presumed mammalian homolog of Hsv2 cause the neurodegenerative disease BPAN, our study thus also helps to understand its underlying principles.<b>Abbreviations:</b> CSC: cargo specific complex, FAS: fatty acid synthase, PAS: phagophore assembly site; PROPPIN: beta-propeller that binds phosphoinositides.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2164-2181"},"PeriodicalIF":14.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147944220","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":"PRKN/parkin-mediated control of SNCA (synuclein alpha) and chaperone-mediated autophagy are defective in cellular, mice models and Parkinson disease-affected brains.","authors":"Lígia Ramos Dos Santos, Eric Duplan, Juliane Debord, Gwendoline Fremont, Julien Minniti, Inger Lauritzen, Eugenie Mutez, Coline Leghay, Marie Christine Chartier-Harlin, Frédéric Checler, Cristine Alves da Costa","doi":"10.1080/15548627.2026.2669458","DOIUrl":"10.1080/15548627.2026.2669458","url":null,"abstract":"<p><p>Pathological accumulation of toxic SNCA species and loss of E3-ligase function of PRKN are two key features observed in Parkinson disease (PD). Here, we established the contribution of an E3-ligase-independent transcriptional function of PRKN in SNCA regulation. PRKN depletion decreased <i>SNCA</i> and <i>GBA1</i> (glucosylceramidase beta 1) mRNA levels and reduced CMA-driven degradation of SNCA, thereby triggering the accumulation of its phosphorylated aggregation-prone toxic species. We established that PRKN controls the CMA player LAMP2A but not HSPA8/HSC70 in isolated lysosomal fractions prepared from human neuronal and mouse fibroblastic cells. Further, we showed that PRKN-associated regulation of LAMP2 is isoform specific. We showed that PRKN-mediated control of SNCA, GBA1 and LAMP2A occurs <i>in vivo</i> and is impaired in the paraquat-treated PD mice model. We showed that the levels of phosphorylated SNCA and PRKN are correlated in sporadic PD human brain samples and that fibroblasts of patients carrying pathogenic <i>PRKN</i> mutations exhibit impaired CMA activity. Our study decrypts a new molecular mechanism linking three PD major therapeutic targets. It enriches the portfolio of transcriptional targets of PRKN and establishes PRKN as a novel CMA regulator. Further, it shows that PRKN controls both direct and indirect (GBA1-dependent) transcriptional regulation of <i>SNCA</i>. This novel molecular cascade opens potential new avenues in PD treatment.<b>Abbreviations:</b> ChIP: chromatin immunoprecipitation; CMA: chaperone-mediated autophagy; ΔPkPr: deleted <i>PRKN</i>-RE <i>Snca</i> promoter; GBA1: glucosylceramidase beta 1; HAP1: human haploid cell; <i>GBA1</i>^<i>+</i>: human haploid control cells; <i>GBA</i>^-: human haploid invalidated for <i>GBA1</i> cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; MEF: mouse embryonic fibroblast; <i>Prkn</i>^<i>+/+</i>: MEF and mice <i>Prkn</i> control; <i>prkn</i>^<i>-/-</i>: MEF and mice <i>prkn</i> knockout; PD: Parkinson disease; PQ: paraquat; PRKN: parkin RBR E3 ubiquitin protein ligase; <i>PRKN</i>-RE: <i>PRKN</i> responsive element; <i>PRKN [SC]</i>: PRKN control; <i>PRKN [KD]</i>: <i>PRKN</i>-depleted; SNCA: synuclein alpha; SNCA [M]: monomeric synuclein alpha; SNCA [O]: oligomeric synuclein alpha; SNCA p-S129: phosphorylated synuclein alpha, SPD: sporadic Parkinson disease; TF: transcription factor; TH: tyrosine hydroxylase; <i>WTPr</i>: wild-type <i>Snca</i> promoter.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2405-2423"},"PeriodicalIF":14.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13502014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847427","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":"FASN mediates crosstalk between autophagy and lipid metabolism via the AMPK-MTOR pathway in early age-related macular degeneration.","authors":"Jinyu Cai, Yanmei Jiang, Xingyu Liu, Tao Yang, Peizeng Yang, Ling Chen","doi":"10.1080/15548627.2026.2673559","DOIUrl":"10.1080/15548627.2026.2673559","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) involves sub-retinal pigment epithelium (sub-RPE) lipid deposition in the early stage, with dysregulated lipid metabolism and impaired macroautophagy/autophagy implicated, yet the molecular mechanisms underlying their interaction remain unclear. In this study, transcriptomic analysis of human macular tissues identified FASN (fatty acid synthase), a regulator of lipid metabolism and lysosomal function, as a significantly upregulated key hub gene in early AMD. In <i>apoe</i>^<i>-/-</i> mice fed a high-fat diet (HFD), retina-RPE-choroid complexes revealed elevated FASN alongside autophagy suppression, lysosomal dysfunction, and lipid accumulation. In vitro, FASN protein levels increased in RPE cells treated with the autophagy inhibitor 3-methyladenine (3-MA), but decreased with the autophagy activator rapamycin (RAPA), without transcriptional changes; lysosomal blockade with chloroquine (CQ) induced FASN accumulation, which was significantly delayed following autophagy inhibition. These findings indicate that FASN accumulation results from insufficient autophagic degradation. Conversely, FASN knockdown or pharmacological inhibition enhanced autophagic flux and promoted lysosomal lipid clearance in RPE cells. Mechanistically, FASN inhibition increased AMPK phosphorylation and decreased MTOR activity, thereby facilitating autophagy and lipophagy. Collectively, our findings reveal a self-amplifying pathological circuit in early AMD: autophagy impairment drives FASN accumulation, which in turn exacerbates lysosomal dysfunction and lipid accumulation. Targeting the FASN-AMPK-MTOR axis may offer a promising therapeutic strategy for early AMD.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2248-2267"},"PeriodicalIF":14.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977883","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":"Intracellular lipopolysaccharide binds RETREG1/FAM134B to regulate ER remodeling upon bacterial infection.","authors":"Yi-Lin Cheng, João Mello-Vieira, Adriana Covarrubias-Pinto, Alexis Gonzalez, Santosh Kumar Kuncha, Chun Kew, Kaiyi Zhang, Muhammad Awais Afzal, Nour Diab, Sophia Borchert, Siou-Ying Hong, Timothy Chun Huang, Wenbo Chen, Uxía Gestal Mato, Mathias Walter Hornef, Christian A Hübner, Michael Hensel, Ivan Dikic","doi":"10.1080/15548627.2026.2669978","DOIUrl":"10.1080/15548627.2026.2669978","url":null,"abstract":"<p><p>Selective autophagy of the endoplasmic reticulum (ER), termed ERphagy or reticulophagy, plays a key role in organelle remodeling and cellular homeostasis. However, whether and how ERphagy is regulated during Gram-negative bacteria infection to influence host responses remains unclear. Here, we show that <i>Salmonella enterica</i> serovar Typhimurium releases lipopolysaccharide (LPS) that colocalizes with RETREG1/FAM134B, a reticulon-like ER-resident receptor for ERphagy. Cytosolic delivery of LPS, either during infection or via transfection, markedly increases RETREG1- and LC3B-decorated ER fragments. Mechanistically, affinity-isolation assays demonstrate that LPS directly binds RETREG1 through interactions between lipid A and positively charged residues within its amphipathic helices and C-terminal region. This interaction promotes RETREG1 oligomerization and drives ER membrane fragmentation, a process further amplified by the O-antigen moiety of LPS. The resulting ER fragments accumulate around LC3-positive <i>Salmonella</i>-containing vacuoles, facilitating bacterial clearance. Importantly, both intracellular and extracellular <i>Salmonella</i> exploit outer membrane vesicles (OMVs) to deliver LPS into the host cytosol, triggering RETREG1 activation and ER remodeling. Collectively, our findings reveal a previously unrecognized host response by which LPS of Gram-negative bacteria are sensed by the host ERphagy machinery to promote xenophagy and enhance antibacterial defense.<b>Abbreviations</b>: AH: amphipathic helix; BMDMs: bone-marrow-derived macrophages; Co-IP: co-immunoprecipitation; BafA1: bafilomycin A₁; Cterm: C-terminal region (Cterm); CFU: colony-forming units; DAPI: 4',6-diamidino-2-phenylindole; ER: endoplasmic reticulum; EPEC: enteropathogenic <i>Escherichia coli</i>; GBP: guanylate binding protein; Gm12250/IRGB10: predicted gene 12250; KDO: keto-3-deoxy-octonate; LPR: lipid-to-protein ratio; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; mtLIR: LC3B-interacting region mutant; MDP: muramyl dipeptide; OMVs: outer membrane vesicles; O-Ag: O-antigen; OmpA: outer membrane protein A; RHD: reticulum homology domain; R-LPS: rough-LPS; S-LPS: smooth-LPS; SCVs: <i>Salmonella</i>-containing vacuoles; SFB: S-protein-FLAG-streptavidin binding peptide; TM: transmembrane domain; TEM: transmission electron microscopy; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2101-2118"},"PeriodicalIF":14.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876826","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}