Autophagy最新文献

{"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":"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":"1850-1852"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756518","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":"First responder to starvation: microreticulophagy clears aberrant membrane proteins in quick bites.","authors":"Yaneris M Alvarado Cartagena, Valeriya Gyurkovska, Nava Segev","doi":"10.1080/15548627.2025.2487675","DOIUrl":"10.1080/15548627.2025.2487675","url":null,"abstract":"<p><p>Cells can use two different pathways for recycling their non-essential components in the lysosome during nutritional stress: macroautophagy and microautophagy. While the well-established macroautophagy pathway requires de novo formation of the double-membrane autophagosome, microautophagy involves direct engulfment of cargo by the lysosomal membrane. Recently, using a yeast model, we identified a novel microreticulophagy pathway induced by nutritional stress that selectively clears aberrant membrane proteins that accumulate during normal growth. This effective clearance occurs rapidly and precedes the degradation of normal ER- or mitochondrial-membrane proteins by macroautophagy. We showed that the nutritional-stress induced selective microreticulophagy pathway requires the ubiquitin-ligase Rsp5, its adaptor Ssh4, and the ESCRT complex. Moreover, live-cell fluorescence microscopy with high temporal and special resolution demonstrated that individual microautophagy events occur within seconds. Thus, cells use the effective microreticulophagy pathway to dispose of misfolded or excess membrane proteins as a first response to starvation. If the stress persists, the more costly macroautophagy pathway is activated for degrading normal cellular components. These findings point to an intricate interplay between microautophagy and macroautophagy during nutritional stress, which optimizes stress responses and could have significant implications for understanding how cells maintain homeostasis or progress to disease states.<b>Abbreviation:</b> ER, endoplasmic reticulum; ERAD, ER-associated degradation; QC, quality control; reticulophagy, selective autophagy of the ER.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1853-1855"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766073","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":"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":"1700-1716"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660123","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":"PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology.","authors":"Chuang Zhang, Zhanpeng Huang, Xinyue Huang, Yanni Ma, Yifan Cao, Zhixiong Zhang, Rui Wang, Haigang Ren, Longtai Zheng, Chun-Feng Liu, Guanghui Wang","doi":"10.1080/15548627.2024.2448914","DOIUrl":"10.1080/15548627.2024.2448914","url":null,"abstract":"<p><p>The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology of Parkinson disease (PD). PLK2 (polo like kinase 2) is an evolutionarily conserved serine/threonine kinase that is more abundant in the brains of all family members, is highly expressed in PD, and is linked to SNCA deposition. However, in addition to its role in phosphorylating SNCA, the role of PLK2 in PD and the mechanisms involved in triggering neurodegeneration remain unclear. Here, we found that PLK2 regulated SNCA pathology independently of S129. Overexpression of PLK2 promoted SNCA preformed fibril (PFF)-induced aggregation of wild-type SNCA and mutant SNCA^S129A. Genetic or pharmacological inhibition of PLK2 attenuated SNCA deposition and neurotoxicity. Mechanistically, PLK2 exacerbated the propagation of SNCA pathology by impeding the clearance of SNCA aggregates by blocking macroautophagic/autophagic flux. We further showed that PLK2 phosphorylated S1098 of DCTN1 (dynactin 1), a protein that controls the movement of organelles, leading to impaired autophagosome-lysosome fusion. Furthermore, genetic suppression of PLK2 alleviated SNCA aggregation and motor dysfunction <i>in vivo</i>. Our findings suggest that PLK2 negatively regulates autophagy, promoting SNCA pathology, suggesting a role for PLK2 in PD.<b>Abbreviation</b>: AD: Alzheimer disease; AMPK: AMP-activated protein kinase; CASP3: caspase 3; DCTN1: dynactin 1; LBs: lewy bodies; LDH: lactate dehydrogenase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP2: microtubule associated protein 2; MTOR: mechanistic target of rapamycin kinase; NH4Cl: ammonium chloride; p-SNCA: phosphorylation of SNCA at S129; PD: Parkinson disease; PFF: preformed fibril; PI: propidium iodide; PLK2: polo like kinase 2; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit alpha; shRNA: short hairpin RNA; SNCA: synuclein, alpha; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; TX: Triton X-100; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1623-1643"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960181","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":"H3K36me2 methyltransferase NSD2/WHSC1 promotes triple-negative breast cancer metastasis via activation of ULK1-dependent autophagy.","authors":"Danyang Chen, Xiaohui Chen, Mingqiang Yang, Qiunuo Li, Shaojuan Weng, Siyue Kou, Xi Liu, Guanmin Jiang, Hao Liu","doi":"10.1080/15548627.2025.2479995","DOIUrl":"10.1080/15548627.2025.2479995","url":null,"abstract":"<p><p>Metastasis is the primary cause for treatment failure and poor prognosis in patients with triple-negative breast cancer (TNBC). Macroautophagy/autophagy plays a crucial role in tumor growth and metastasis. Genetic or epigenetic regulation of autophagy-related factors alters autophagy levels, which subsequently promotes cancer progression and affects the therapeutic effectiveness. However, the molecular basis for the transcriptional and epigenetic regulation of autophagy in TNBC progression is poorly understood. In this study, we reveal the histone methyltransferase NSD2/WHSC1 (nuclear receptor binding SET domain protein 2) as a novel epigenetic regulator of autophagy in TNBC progression. We demonstrate that the expression of NSD2 is significantly upregulated in TNBC cells and high NSD2 expression is correlated with poor TNBC survival. Elevated expression of NSD2 significantly promotes TNBC metastasis in multiple TNBC models. Mechanistically, ULK1 (unc-51 like autophagy activating kinase 1) is identified as a novel target of NSD2 and NSD2-mediated histone H3K36me2 methylation directly activates ULK1 transcription in TNBC cells. Notably, NSD2-induced ULK1 expression facilitates autophagosome maturation and increases autophagic flux, thus promoting autophagy-related malignancy progression in TNBC. Furthermore, pharmacological inhibition of NSD2 using MS159 and MCTP-39 significantly suppresses TNBC autophagy, growth, and metastasis both <i>in vivo</i> and <i>in vitro</i>. In conclusion, our findings demonstrate a pivotal epigenetic role for the NSD2-H3K36me2 axis in regulating ULK1 expression and identify a novel NSD2-ULK1-autophagy signaling axis in the promotion of TNBC progression, suggesting that NSD2 inhibition may be an effective treatment strategy for TNBC.<b>Abbreviations</b>: CDH2/N-cadherin: cadherin 2; ChIP: chromatin immunoprecipitation; EMT: epithelial-mesenchymal transition; ESR: estrogen receptor; FN1: fibronectin 1; GEPIA: Gene Expression Profiling Interactive Analysis; H3K36me2: di-methylation at lysine 36 of histone 3; H&E: hematoxylin and eosin; HDM: histone demethylase; HMT: histone methyltransferase; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; IF: Immunofluorescence; IHC: Immunohistochemistry; NSD: nuclear receptor binding SET domain protein; PGR: progesterone receptor; qRT-PCR: quantitative RT-PCR; TCGA: The Cancer Genome Atlas; TNBC: triple-negative breast cancer; TSS: transcription start site; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1824-1842"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652612","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":"MLST8 overexpression in RPE cells disrupts autophagy through novel mechanisms affecting AMD pathogenesis.","authors":"Sridhar Bammidi, Sayan Ghosh, Olivia Chowdhury, Vishnu Suresh Babu, Puja Dutta, Stacey Hose, Debasish Sinha","doi":"10.1080/15548627.2025.2491097","DOIUrl":"10.1080/15548627.2025.2491097","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly, with dysfunction of the retinal pigment epithelium (RPE) central to disease pathogenesis. Using our uniquely developed MLST8 (MTOR associated protein, LST8 homolog) knock-in animal model with RPE-specific overexpression, which drives MTOR (mechanistic target of rapamycin kinase) upregulation, we demonstrate that increased MTOR complexes 1 and 2 in the RPE disrupts macroautophagy/autophagy by suppressing autophagosome formation genes and impairing MAP1LC3/LC3 processing. This leads to autophagosome accumulation and defective autolysosome formation, driving RPE dysfunction and AMD-like pathology, including subretinal debris build up and photoreceptor degeneration. Notably, MTOR inhibition with torin1 treatment or CRYBA1 overexpression rescues these defects, restoring autophagy and RPE integrity. Our findings reveal that autophagy disruption mediated by both MTORC1 and MTORC2 drives AMD-like pathology in our mouse model, establishing autophagy regulation as a promising avenue for therapeutic intervention in this vision-threatening disease.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1856-1858"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047981","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":"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":"1644-1661"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652615","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":"Chaperone-mediated autophagy degrades SERPINA1^E342K/α1-antitrypsin Z variant and alleviates cell stress.","authors":"Jiayu Lin, Xinyue Wei, Yan Dai, Haorui Lu, Yajian Song, Jiansong Ju, Rihan Wu, Qichen Cao, Hao Yang, Lang Rao","doi":"10.1080/15548627.2025.2480037","DOIUrl":"10.1080/15548627.2025.2480037","url":null,"abstract":"<p><p>Chaperone-mediated autophagy (CMA) is a specific form of autophagy that selectively targets proteins containing a KFERQ-like motif and relies on the chaperone protein HSPA8/HSC70 for substrate recognition. In SERPINA1/a1-antitrypsin deficiency (AATD), a disease characterized by the hepatic buildup of the SERPINA1^E342K/ATZ, CMA's role had been unclear. This work demonstrates the critical role that CMA plays in preventing SERPINA1^E342K/ATZ accumulation; suppressing CMA worsens SERPINA1^E342K/ATZ accumulation while activating it through chemical stimulation or LAMP2A overexpression promotes SERPINA1^E342K/ATZ breakdown. Specifically, SERPINA1^E342K/ATZ's ₁₂₁QELLR₁₂₅ motif is critical for HSPA8/HSC70 recognition and LAMP2A's charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of SERPINA1^E342K/ATZ. This selective activation of CMA operates independently of other autophagy pathways and alleviates SERPINA1^E342K/ATZ aggregate-induced cellular stress. In vivo administration of AR7 promotes hepatic SERPINA1^E342K/ATZ elimination and mitigates hepatic SERPINA1^E342K/ATZ aggregation pathology. These findings highlight CMA's critical function in cellular protein quality control of SERPINA1^E342K/ATZ and place it as a novel target for AATD treatment.<b>Abbreviation:</b> AR7: atypical retinoid 7; ATG16L1: autophagy related 16 like 1; AATD: SERPINA1/alpha-1 antitrypsin deficiency; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; MG132: carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; PAS-D: periodic acid-Schiff plus diastase; SERPINA1/A1AT: serpin family A member 1; SERPINA1^E342K/ATZ: Z variant of SERPINA1; TMRE: tetramethyl rhodamine ethyl ester perchlorate.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1662-1679"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671496","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":"ATG2A acts as a tether to regulate autophagosome-lysosome fusion in neural cells.","authors":"Ze Zheng, Cuicui Ji, Hongyu Zhao, Yan G Zhao","doi":"10.1080/15548627.2025.2479427","DOIUrl":"10.1080/15548627.2025.2479427","url":null,"abstract":"<p><p>The macroautophagy/autophagy proteins ATG2A and ATG2B transfer lipids for phagophore membrane growth. They also form stable complexes with WDR45 and WDR45B. Our previous study demonstrated that WDR45 and WDR45B mediate autophagosome-lysosome fusion in neural cells. Given the defective autophagosome formation in cells lacking both ATG2s, their role in later autophagy stages is hard to explore. Here, we report that in neuroblastoma-derived Neuro-2a (N2a) cells, knocking down (KD) <i>Atg2a</i>, but not <i>Atg2b</i>, results in significant accumulation of SQSTM1/p62 and MAP1LC3-II/LC3-II, indicating impaired autophagy. <i>Atg2a</i> deficiency does not affect autophagosome formation, but reduces colocalization of autophagosomal LC3 with late endosomal/lysosomal RFP-RAB7, suggesting impaired autophagosome-lysosome fusion. ATG2A interacts with the SNARE proteins STX17, SNAP29, and VAMP8, facilitating their assembly. Overexpression of ATG2A partially rescues the autophagosome-lysosome fusion defects in <i>Wdr45-</i> and <i>Wdr45b</i>-deficient cells. ATG2 and another tether protein, EPG5, function partially redundantly in mediating autophagosome-lysosome fusion. Thus, ATG2A plays a key role in neural autophagy by tethering autophagosomes with lysosomes for fusion.<b>Abbreviations</b>: AAV: adeno-associated virus; ATG2A^r: RNAi-resistant ATG2A; Baf: bafilomycin A₁; co-IP: co-immunoprecipitation; CQ: chloroquine; DKD: double knockdown; DKO: double knockout; ER: endoplasmic reticulum; KD: knockdown; KO: knockout; MIL: membrane-impermeable Halo ligand; MPL: membrane-permeable Halo ligand; N2a: Neuro-2a; NC negative control; PG: phagophore; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; TEM: Transmission electron microscopy; TM: transmembrane domain; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1767-1778"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626688","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":"Npl3 is required for efficient autophagosome-vacuole fusion.","authors":"Zhangyuan Yin, Zhihai Zhang, Xu Liu, Daniel J Klionsky","doi":"10.1080/15548627.2025.2537559","DOIUrl":"10.1080/15548627.2025.2537559","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a highly conserved catabolic membrane trafficking process through which various intracellular constituents, from proteins to organelles, are targeted for vacuolar/lysosomal degradation. Autophagy is tightly regulated both temporally and in magnitude at multiple levels to prevent either excessive or insufficient activity. To date, only a few RNA-binding proteins have been characterized as regulating the expression of genes essential for autophagy, and the contribution of post-transcriptional regulation in autophagy activity remains poorly understood. Here, through a genetic screen for autophagy-defective mutants, we identified Npl3, a nucleus-cytoplasm shuttling mRNA-binding protein, as essential for both bulk and selective types of autophagy. Deletion of <i>NPL3</i> does not affect autophagosome biogenesis, closure, or maturation; however, it severely impairs autophagosome-vacuole fusion and results in minimal autophagosome turnover. We further demonstrated that this regulation depends on the RNA-binding domain of Npl3 and its capability for nuclear re-import. Together, our results reveal a novel layer of post-transcriptional regulation of autophagy.<b>Abbreviations:</b> Atg,autophagy related; HOPS: homotypic fusion and protein sorting; prApe1: precursor aminopeptidase I; RBP, RNA-binding protein; RRM, RNA-recognition motif; SNARE: soluble NSF attachment protein receptor; PAS: phagophore asse.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-12"},"PeriodicalIF":14.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692747","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}