Autophagy最新文献

{"title":"UCHL3 drives ferroptosis in nucleus pulposus cells by deubiquitinating HMGB1 to activate NCOA4-mediated ferritinophagy.","authors":"Tao Hu, Peng Cui, Xuan Zhao, Wei Wang, Yingdong Ma, Xinli Hu, Haojie Zhang, Zuoran Fan, Dongfan Wang, Qingyang Huang, Fumin Pan, Haixia Huang, Chunying Cui, Xiaolong Chen, Yuluo Rong, Shibao Lu","doi":"10.1080/15548627.2026.2679172","DOIUrl":"10.1080/15548627.2026.2679172","url":null,"abstract":"<p><p>Ferroptosis contributes to intervertebral disc degeneration (IVDD), yet its upstream regulatory mechanisms in nucleus pulposus cells (NPCs) remain unclear. Here, we identify a novel UCHL3-HMGB1-NCOA4 signaling axis that drives NPC ferroptosis. Transcriptomic and clinical analyses reveal that UCHL3 is upregulated in degenerative discs, with its expression correlating positively with both IVDD severity and ferroptosis markers. Mechanistically, UCHL3 deubiquitinates and stabilizes HMGB1 by cleaving Lys48-linked polyubiquitin chains, thereby promoting the accumulation of cytoplasmic HMGB1. This stabilized HMGB1 activates NCOA4-mediated ferritinophagy, initiating ferroptosis. Silencing <i>UCHL3</i> or <i>NCOA4</i> mitigates these effects. Furthermore, a polydopamine-based nanoplatform (PDA@si-<i>UCHL3</i>) achieves dual therapeutic action, silencing <i>UCHL3</i> while scavenging ROS and chelating iron, which effectively inhibits ferroptosis and alleviates IVDD in rats. These findings establish UCHL3 as a pivotal regulator of NPC ferroptosis and highlight PDA@si-<i>UCHL3</i> as a promising therapeutic strategy for IVDD.<b>Abbreviations:</b> AAV: adeno-associated virus; CCK-8: cell counting kit-8; Co-IP: co-immunoprecipitation; DUBs: deubiquitinating enzymes; ECM: extracellular matrix; GPX4: glutathione peroxidase 4; GSH: glutathione; HE: hematoxylin and eosin; HMGB1: high mobility group box 1; IF: immunofluorescence; IHC: immunohistochemistry; IP/MS: immunoprecipitation mass spectrometry; IVDD: intervertebral disc degeneration; IVDs: intervertebral discs; MRI: magnetic resonance imaging; NCOA4: nuclear receptor coactivator 4; NP: nucleus pulposus; NPCs: nucleus pulposus cells; PDA: polydopamine; PG: Pfirrmann grading; ROS: reactive oxygen species; siRNA: small interfering RNAs; SO-FG: Safranin O-Fast Green; TBHP: tert-butyl hydroperoxide; TEM: transmission electron microscope; UCHL3: ubiquitin C-terminal hydrolase L3; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2887-2907"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147990335","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":"PRRSV NSP2 hijacks host lipophagy via a LIPE-PNPLA2-AMPK-MTOR axis to promote viral replication.","authors":"Zhenbang Zhu, Qianwen Lin, Xinyu Zhang, Meng Zhang, Yifan Yan, Wenqiang Wang, Wei Wen, Xiangdong Li","doi":"10.1080/15548627.2026.2676077","DOIUrl":"10.1080/15548627.2026.2676077","url":null,"abstract":"<p><p>Porcine reproductive and respiratory syndrome virus (PRRSV) exploits host lipid metabolism to support its replication by harnessing lipids and their metabolic derivatives. Lipophagy, a selective autophagic process responsible for lipid droplet (LD) degradation and cellular lipid homeostasis regulation, has been implicated in viral infections, however, its specific role in PRRSV replication has not been investigated. In this study, we found that PRRSV infection triggered lipophagy, resulting in LD depletion and elevated intracellular free fatty acids. Mechanistically, the viral protein NSP2 was essential for PRRSV-induced lipophagy by directly interacting with LD-associated lipases LIPE and PNPLA2, facilitating their binding to MAP1LC3/LC3 via LIR motifs. Both interactions were required for lipophagy-dependent viral replication. Furthermore, we demonstrated that the AMPK signaling pathway critically regulated PRRSV-induced lipophagy. AMPK activation promoted viral replication, whereas its inhibition impaired both lipophagy and viral propagation. Conversely, MTOR signaling acted as a negative regulator of lipophagy, with MTOR inhibition promoting this process. Collectively, these findings established that PRRSV hijacked host lipophagy to facilitate viral replication through NSP2-LIPE-PNPLA2 interactions and an AMPK-MTOR signaling pathway. Our work provided mechanistic insights into viral pathogenesis and highlighted potential therapeutic targets for PRRSV prevention and control.<b>Abbreviations</b>: AMPK: AMP-activated protein kinase; co-IP: co-immunoprecipitation; CQ: chloroquine; CMA: chaperone-mediated autophagy; FFA: free fatty acid; HEK-293T: human embryonic kidney 293T; hpi: hour post infection; LAMP1: lysosome associated membrane protein 1; LD: lipid droplet; LIPA/LAL: lipase A, lysosomal acid type; LIPE/HSL: lipase E, hormone sensitive type; LIRs: LC3-interacting regions; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGLL: monoglyceride lipase; MG132: carbobenzoxyl-l-leucyl-l-leucyl-l-leucinal; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NSPs: non-structural proteins; ORFs: open reading frames; PNPLA2/ATGL: patatin-like domain 2, triacylglycerol lipase; PRRSV: porcine reproductive and respiratory syndrome virus; SQSTM1/p62: sequestosome 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2615-2641"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148038643","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":"Correction.","authors":"","doi":"10.1080/15548627.2025.2491878","DOIUrl":"10.1080/15548627.2025.2491878","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"i"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046287","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":"Dual mechanism of human ATG10S in suppressing MEF2A-Driven pro-inflammatory responses.","authors":"Miao-Qing Zhang, Zheng-Hao Wang, Jing-Pu Zhang","doi":"10.1080/15548627.2026.2676074","DOIUrl":"10.1080/15548627.2026.2676074","url":null,"abstract":"<p><p>Cytokine storm, characterized by excessive release of pro-inflammatory cytokines, contributes to the severity and exacerbation of various diseases. Current therapies targeting individual cytokines prove inadequate due to the complex and multifactorial nature of inflammatory cascades. Here, we report human ATG10S, a novel isoform of the autophagy-related protein ATG10, as a potential inhibitor of cytokine storms. Using SARS-CoV-2 Spike (S) protein- or LPS-induced pro-inflammatory zebrafish and co-cultured human cell models, we found that ATG10S significantly reduced the expression of key pro-inflammatory cytokines (IFNA, IFNG, IL1B, IL6, TNF/TNFA, IL8, and CCL2), all transcriptionally regulated by MEF2A (myocyte enhancer factor 2A). Mechanistically, ATG10S bound directly to MEF2A at residues D61/D63, facilitating its selective autolysosomal degradation through MAP1LC3B/LC3B interaction, while it also competed with MAPK7/ERK5 for MEF2A binding to disrupt the TLR4-MAPK7-MEF2A signaling axis. This dual mechanism reduced both MEF2A protein levels and transcriptional activity, thereby attenuating cytokine overproduction. Importantly, ATG10S restored autophagic flux impaired by inflammatory stimuli and exhibited high specificity, sparing unrelated transcription factors. These findings established MEF2A as a critical regulator of the cytokine storm and revealed ATG10S as a distinctive macroautophagy/autophagy-linked immunomodulator that integrated selective autophagic degradation and transcriptional interference. Our study provides mechanistic insight into autophagy-mediated inflammatory regulation and highlights ATG10S as a promising therapeutic candidate for cytokine storm-associated diseases.<b>Abbreviations</b>: ATG: autophagy related; co-IP: co-immunoprecipitation; CQ: chloroquine; dpf: days post-fertilization; ELISA: enzyme-linked immunosorbent assay; hpi: hours post-injection; LC3B: microtubule-associated protein 1 light chain 3 beta; LIR: LC3-interacting region; LPS: lipopolysaccharide; MAPK7/ERK5: mitogen-activated protein kinase 7; MDMs: macrophages; MEF2A: myocyte enhancer factor 2A; MO: morpholino; S: spike protein; SQSTM1: sequestosome 1; TLR4: toll like receptor 4.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2576-2597"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147965763","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":"Influenza a virus NS2 suppresses NFKB/NF-κB signaling to facilitate viral replication by mediating the autophagic-degradation of IKBKG/NEMO.","authors":"Bo Zhang, Lebin Han, Chenying Cui, Jiaxin Huang, Qiyun Zhu, Caoqi Lei, Shuai Xu","doi":"10.1080/15548627.2026.2676801","DOIUrl":"10.1080/15548627.2026.2676801","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Influenza A virus (IAV) is an important zoonotic pathogen responsible for substantial respiratory morbidity and mortality. Elucidating the mechanisms by which IAV evades host innate immunity is critical for developing novel antiviral strategies. Although the IAV non-structural protein 2 (NS2) is well-characterized for the export of viral ribonucleoproteins (vRNPs) from the host cell nucleus, the function of NS2 in evading host innate immunity, especially the NFKB/NF-κB (nuclear factor kappa B) signaling pathway, remains poorly understood. The present study uncovered that NS2 is a novel viral inhibitor of the NFKB pathway. Mechanistically, NS2 interacted with and mediated the degradation of the NFKB essential modulator (IKBKG/NEMO), thereby suppressing downstream signal transduction. The macroautophagy/autophagy receptor OPTN (optineurin) was exploited by NS2 to mediate the selective autophagic degradation. Furthermore, the K72 residue was critical for the NS2-mediated degradation of IKBKG/NEMO, as the K72R substitution in NS2 disrupted the IKBKG/NEMO-NS2 interaction and abrogated the autophagic degradation. In addition, NS2&lt;sup&gt;K72R&lt;/sup&gt; mutant virus displayed less viral load and milder pathogenicity in mice. In conclusion, these findings highlighted the novel biological function of IAV NS2 in exploiting selective autophagy to evade host defenses, and offered a potential target for controlling IAV infections.&lt;b&gt;Abbreviations&lt;/b&gt;: 3-MA: 3-methyladenine; AIV: avian influenza virus; ATG7: autophagy related 7; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; co-IP: co-immunoprecipitation; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; DAPI: 4', 6-diamidino-2-phenylindole, dihydrochloride; dsRNA: double-stranded RNA; dpi: days post-infection; EID&lt;sub&gt;50&lt;/sub&gt;: 50% egg infective dose; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; hpi: hours post-infection; IAV: influenza A virus; IFN: interferon; IKBKB/IKKβ: inhibitor of nuclear factor kappa B kinase subunit beta; IFNG: interferon gamma; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase subunit gamma; IKK: IκB kinase; IP: immunoprecipitation; IRF3: interferon regulatory factor 3; IRF7: interferon regulatory factor 7; LAMP1: lysosome associated membrane protein 1; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K14/NIK: mitogen-activated protein kinase kinase kinase 14; MAVS: mitochondrial antiviral signaling protein; MLD&lt;sub&gt;50&lt;/sub&gt;: 50% mouse lethal dose; MOI: multiplicity of infection; MRV/Sendai virus: murine respirovirus; NBR1: NBR1 autophagy cargo receptor; NEP: nuclear export protein; NFKB/NF-κB: nuclear factor kappa B; NFKB2/p100: nuclear factor kappa B subunit 2; NFKBIA/IκBα: NFK inhibitor alpha; NP: nucleoprotein; NS1: non-structural protein 1; OPTN: optineurin; PB1: basic polymerase 1; PBS: phosphate-buffered saline; poly(I:C): polyriboinosini","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2679-2694"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977881","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":"TRP53/p53 protects adult hippocampal neural stem cells from psychological stress by preventing autophagic cell death.","authors":"Seonghee Jung, Hyeonjeong Jeong, Seongwon Choe, Jieun Choi, Kyung Min Chung, Joo Yeon Kim, Eunsoo Lee, Han-Woong Lee, Youngtae Jeong, Eun-Kyoung Kim, Woong Sun, Seong-Woon Yu","doi":"10.1080/15548627.2026.2676073","DOIUrl":"10.1080/15548627.2026.2676073","url":null,"abstract":"<p><p>Psychological stress impairs adult hippocampal neurogenesis (AHN) and contributes to cognitive dysfunction. Previously, we reported that chronic psychological stress or the stress hormone corticosterone (CORT) induces autophagic cell death (ACD) in adult hippocampal neural stem cells (ahNSCs). However, the regulatory mechanisms underlying this process remain largely unknown. The tumor suppressor gene <i>Trp53/p53</i> is abundantly expressed in ahNSCs, yet its function under stress conditions has not been fully elucidated. Here, we demonstrate that, contrary to its well-established pro-apoptotic role, TRP53 acts as a survival factor that protects ahNSCs from stress-induced ACD. Conditional deletion of <i>Trp53</i> in neural stem cells heightened vulnerability to chronic restraint stress (CRS), resulting in worsened memory deficits and mood disturbances compared to wild-type controls. Mechanistically, CORT facilitated MAP1LC3/LC3-mediated autophagic degradation of TRP53 through its LC3-interacting region (LIR), thereby promoting ACD. However, overexpression of either wild-type TRP53 or a degradation-resistant LIR mutant suppressed ACD by interfering with the ATG14-containing PIK3C3/VPS34 complex. Moreover, treatment with RITA, a small-molecule activator of TRP53, disrupted the TRP53-LC3 interaction, stabilized TRP53 levels, and protected ahNSCs from ACD, ultimately preventing CRS-induced cognitive impairment in the hippocampus. These findings identify TRP53 as a key negative regulator of ACD in ahNSCs and suggest that TRP53-stabilizing small molecules could represent a novel class of antidepressant therapies by preserving AHN.<b>Abbreviations</b>: ahNSC: adult hippocampal neural stem cell; AHN: adult hippocampal neurogenesis; ACD: autophagic cell death; BafA1: bafilomycin A₁; ACTB actin, beta; CRS chronic restraint stress; c.CASP3: cleaved caspase 3; cKO conditional knockout; CORT: corticosterone; DG: dentate gyrus; i.p: intraperitoneal; KO: knockout; LABORAS: Laboratory Behavior Observation Registration and Analysis System; LIR LC3-interacting region; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MDM2: MDM2 proto-oncogene; NSC: neural stem cell; PFA: paraformaldehyde; PLA: proximity ligation assay; RITA: reactivation of TRP53 and induction of tumor cell apoptosis; SGK: serum/glucocorticoid regulated kinase; SGZ: subgranular zone; STS: staurosporine; TAM: tamoxifen; TRP53: transformation related protein 53; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; UVRAG: UV radiation resistance associated.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2559-2575"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977843","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":"Thr308-dephosphorylated AKT1 licenses SQSTM1-LC3C-mediated antiviral autophagy.","authors":"Zeyuan Hu, Lulu Lin, Yalan Zhong, Chunyan Li, Yahui Li, Haichong Wu, Jiyong Zhou, Boli Hu","doi":"10.1080/15548627.2026.2677195","DOIUrl":"10.1080/15548627.2026.2677195","url":null,"abstract":"<p><p>AKT1 is classically known as a serine/threonine kinase controlling cell survival and proliferation, yet its kinase-independent functions remain poorly understood. Here we show that recognition of dsRNA viral capsids by membrane-associated HSP90AA1 disrupts the HSP90-AKT1 interaction, inducing AKT1 dephosphorylation at Thr308. This non-phosphorylated AKT1 acts as a scaffold to recruit PDPK1 and SQSTM1, enabling PDPK1-dependent phosphorylation of SQSTM1 at Ser349 and selective loading of viral capsids into LC3C-positive phagophores for degradation. An IBDV capsid mutant defective in SQSTM1 binding escapes this pathway. In vivo, expression of non-phosphorylatable AKT1 suppresses rotavirus replication in a SQSTM1-dependent manner. These findings identify an HSP90-initiated, kinase-independent AKT1 signaling axis that licenses antiviral macroautophagy/autophagy.<b>Abbreviations:</b> AKT1: AKT serine/threonine kinase 1; CQ: chloroquine; dpi: days post-infection; dsRNA: double-stranded RNA; GABARAPL1: GABA type A receptor associated protein like 1; hpi: hour post infection; HSP90AA1: heat shock protein 90 alpha family class A member 1; IBDV: infectious bursal disease virus; KO: knockout; LIR: LC3-interacting region; MAP1LC3C/LC3C: microtubule associated protein 1 light chain 3 gamma; MOI: multiplicity of infection; PDPK1: 3-phosphoinositide dependent protein kinase 1; rVP2: recombinant His-tagged VP2; rVP4: recombinant His-tagged VP4; RV: rotavirus; SQSTM1: sequestosome 1; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2831-2845"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977873","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":"CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.","authors":"Wei Zhou, Maggie Menglan Zhang, Willcyn Tang, Brijesh Kumar Singh, Zhiwei Zhang, Lei Zhou, Jaron Kim Wee Goh, Faith Rui En Tan, Jingxiu Huang, Qiaoyang Sun, Bin Xiao, Gupta Priyanka, Alfred Xuyang Sun, Li Zeng, Han-Ming Shen, Eng King Tan","doi":"10.1080/15548627.2026.2678427","DOIUrl":"10.1080/15548627.2026.2678427","url":null,"abstract":"<p><p>Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHCHD2 and CHCHD10 mutations caused neurodegeneration in model animals as seen in patients, but their pathophysiological roles remain elusive. Here we reported a direct role of CHCHD2 and CHCHD10 in autophagy. We identified a protein complex composing of CHCHD2-CHCHD10-C1QBP/p32-Atg8-family proteins (ATG8s), in which each molecule interacted with another. CHCHD2, CHCHD10 and C1QBP/p32 associated with ATG8s, preferentially, GABARAPs. Disease-associated CHCHD2 and CHCHD10 mutations exhibited varied interaction with ATG8s. By binding to GABARAPs, CHCHD2 and CHCHD10 underwent autophagic degradation, and recruited the ULK1 complex. Autophagy initiation defects occurred upon transient knockdown of <i>CHCHD2</i>, and also in human iPSC-derived <i>CHCHD2</i>^-/- or <i>CHCHD2</i>^<i>T61I</i> dopaminergic neurons. Importantly, CHCHD2 and CHCHD10 promoted autophagy. CHCHD2 reduced protein aggregates in cells and toxic SNCA/α-synuclein species in mouse striatum. Our study thus revealed mitochondrial proteins CHCHD2 and CHCHD10 as both autophagy substrates and autophagy activators and laid groundwork for therapy targeting patients with neurodegeneration.<b>Abbreviations</b>: AA: amino acid; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG8: mammalian Atg8-family protein; ATG13: autophagy related 13; bafA1: bafilomycin A₁; C1QBP<b>/</b>p32/gC1qR<b>/</b>HABP1: complement component 1, q subcomponent binding protein; CHCHD2/MNRR1/MIX17B: coiled-coil-helix-coiled-coil-helix domain containing 2; CHCHD10/MIX17A: coiled-coil-helix-coiled-coil-helix domain containing 10; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CRISPR: clustered regularly interspaced short palindromic repeats; CQ, chloroquine; DA: dopaminergic; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; RB1CC1/FIP200: RB1 inducible coiled-coil 1; FTD: frontotemporal dementia; GABARAP: gamma-aminobutyric acid receptorbassociated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; hESC: human embryonic stem cells; iPSC: induced pluripotent stem cell; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LIR: LC3-interacting region; PD: Parkinson disease; SQSTM1/p62: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein; TH: tyrosine hydroxylase; TMR, tetramethylrhodamine; WT: wild type; UB: ubiquitin; ULK1: unc-51 like kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2947-2976"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148019285","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":"Folic acid protects against <i>Toxoplasma gondii</i> antigen-induced vascular injury via the CD36-autophagy-lysosomal axis.","authors":"Jingfan Qiu, Jiang Jiang, Yingyi Quan, Chenxi Zhang, Nan Gao, Kehan Wang, Jing Guo, Wei Shi, Guifang Wang, Linfeng Jiang, Yang Yang","doi":"10.1080/15548627.2026.2676795","DOIUrl":"10.1080/15548627.2026.2676795","url":null,"abstract":"<p><p>Whether and how pathogen-derived antigens themselves drive vascular injury remains an unresolved question in infection biology and cardiovascular research. Using murine model and human pluripotent stem cell-derived vascular organoids (VOs), we demonstrate that <i>Toxoplasma gondii</i> (<i>T. gondii</i>) infection or exposure to its soluble tachyzoite antigens (STAg) compromises vascular integrity, leads to the impairment of endothelium, and heightens inflammation. Mechanistically, STAg upregulates the scavenger receptor CD36 on endothelial cells (ECs), reprogramming them toward a scavenger endothelial cell (SEC)-like phenotype. This shift enhances CD36‑dependent antigen uptake and subsequently perturbs the macroautophagy/autophagy-lysosomal pathway (ALP), culminating in cellular homeostasis disruption. Interestingly, prophylactic folic acid (FA) ameliorates <i>T. gondii</i> STAg-induced vascular injury. FA acts by suppressing CD36 expression, thereby limiting STAg uptake and attenuating ALP hyperactivation, together preserving vascular integrity at the molecular, structural, and metabolic levels. To our knowledge, this study provides the first evidence that pathogen-derived proteins can reprogram ECs into an SEC-like phenotype in a CD36‑dependent manner, with subsequent dysfunction of ALP. Our findings not only identify pathogen-derived proteins as novel mediators of vascular injury but also establish the CD36-ALP axis as a promising therapeutic target. Furthermore, we propose FA as a potent vascular-protective agent.<b>Abbreviation</b>: ALP: autophagy-lysosomal pathway; Chlo: chloroquine; ECs: endothelial cells; ECM: extracellular matrix; ER: endoplasmic reticulum; FA: folic acid; RAPA: rapamycin; SMCs: smooth muscle cells; STAg: soluble tachyzoite antigens; <i>T.</i> <i>gondii</i>: <i>Toxoplasma gondii</i>; TLRs: toll-like receptors; VOs: vascular organoids.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2657-2678"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977865","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":"Organelle contact reorganization drives calcium-dependent autophagy under proteostatic stress.","authors":"Yubin Ko, Minjeong Ko, Marius Ueffing, Hye Jin Kang, Ho Jeong Kwon","doi":"10.1080/15548627.2026.2677184","DOIUrl":"10.1080/15548627.2026.2677184","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Disruption of proteostasis is a defining feature of cancer and other chronic diseases. The AAA+ ATPase VCP/p97 (valosin containing protein) is a key regulator of proteostasis by disassembling ubiquitinated substrates for degradation. VCP overexpression supports cancer cell survival and correlates with poor prognosis, promoting the development of VCP inhibitors as anti-cancer agents. However, the molecular basis for cancer-selective vulnerability of VCP inhibition remains unclear. Here, we demonstrate that allosteric VCP inhibition triggers cell-type specific macroautophagy/autophagy through dynamic reorganization of organelle contact sites. In human umbilical vein endothelial cells (HUVECs), VCP inhibition induces adaptive autophagy through coordinated reorganization of plasma membrane (PM)-ER-mitochondria contacts. Controlled opening of the mitochondrial permeability transition pore (mPTP) releases calcium into the cytosol, activating AMP-activated protein kinase (AMPK) and TFEB pathways, collectively enhancing autophagic flux and sustaining endothelial survival. Critically, calcium-activated kinase inhibitor or calcium chelators blocked VCP inhibitor-induced autophagy in HUVECs, confirming calcium signaling as the central mediator of adaptive autophagy. In contrast, HCT116 colon cancer cells fail to maintain calcium homeostasis under VCP inhibition, leading to mitochondrial calcium overload, defective autophagy, and cell death. Together, our findings identify organelle contact reorganization and calcium homeostasis as key determinants of cell fate under conditions of proteotoxic stress, revealing how VCP inhibition selectively suppresses tumor progression while preserving vascular integrity that could enhance drug delivery and reduce tumor hypoxia.&lt;b&gt;Abbreviations&lt;/b&gt;: ATF4: activating transcription factor 4; ATG3: autophagy related 3; ATG7: autophagy related 7; ATP: adenosine triphosphate; CAMKK2: calcium/calmodulin dependent protein kinase 2; CETSA: cellular thermal shift assay; CQ: chloroquine; CTS: cryptotanshinone; DDIT3/CHOP: DNA damage inducible transcript 3; DQ-BSA: dye quenched-bovine serum albumin; EIF2A: eukaryotic initiation factor 2A; ER: endoplasmic reticulum; ERAD: endoplasmic reticulum-associated protein degradation; HCT116: human colon carcinoma cell line; HSPA5: heat shock protein family A (Hsp70) member 5; HUVECs: human umbilical vein endothelial cells; ITPR1/IP&lt;sub&gt;3&lt;/sub&gt;R1: inositol 1,4,5-trisphosphate receptor type 1; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; mPTP: mitochondrial permeability transition pore; MT-ND1: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1; MTOR: mechanistic target of rapamycin kinase; ORAI1: ORAI calcium release-activated calcium modulator 1; PLA: proximity ligation assay; PM: plasma membrane; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit alpha; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; STIM1: stromal interaction mol","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2789-2808"},"PeriodicalIF":14.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977832","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}