Autophagy最新文献

{"title":"Dysfunctional autophagy triggers STING1 activation to exacerbate cartilage degeneration in obesity-associated osteoarthritis.","authors":"Xiaomin Kang, Wenjuan Liu, Xiao Ma, Dongxu Feng, Hongzhi Sun, Shufang Wu","doi":"10.1080/15548627.2025.2541388","DOIUrl":"https://doi.org/10.1080/15548627.2025.2541388","url":null,"abstract":"<p><p>Obesity, a major risk factor for osteoarthritis (OA), is related to increased circulating levels of free fatty acids (FFAs). However, the molecular mechanism underlying this metabolic OA phenotype remains unknown. We found that mice fed a high-fat diet (HFD) became obese and developed OA in their knee joints. Macroautophagy/autophagy activity was significantly reduced in articular cartilage of mice fed an HFD or in chondrocytes exposed to FFAs. Using conditional knockout (cKO) mice with cartilage-specific deletion of <i>Atg7</i> to inhibit autophagy <i>in vivo</i> and sh<i>Atg7</i>-lentiviral-transduced chondrocytes in <i>vitro</i>, we showed that autophagy deficiency aggravated HFD-induced OA progression and chondrocyte extracellular matrix (ECM) degradation. Mechanistically, STING1 was degraded in an autophagy-dependent manner. Autophagy deficiency increased STING1 levels, in turn activating the STING1-TBK1-IRF3 and MAP2K3/MKK3-MAPK/p38 signaling pathways, thereby triggering cartilage ECM degradation. These findings suggested that the HFD-autophagy-STING1 axis played a pivotal role in OA development, providing a potential therapeutic strategy for obesity-associated OA.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736000","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":"TM9SF3 is a mammalian Golgiphagy receptor that safeguards Golgi integrity and glycosylation fidelity.","authors":"Jiejie Yang, Yixian Cui","doi":"10.1080/15548627.2025.2539928","DOIUrl":"10.1080/15548627.2025.2539928","url":null,"abstract":"<p><p>Selective autophagy of the Golgi apparatus, or Golgiphagy, depends on receptor proteins that recognize and deliver fragmented Golgi membranes into phagophores for lysosomal degradation. We recently identified TM9SF3, a Golgi-resident transmembrane protein, as a receptor mediating this process under nutrient stress and various Golgi stress conditions. TM9SF3 binds to all six mammalian Atg8 (ATG8) proteins <i>via</i> multiple N-terminal LC3-interacting regions (LIRs). Knockout of <i>TM9SF3</i> inhibits nutrient stress-induced Golgi fragmentation, reduces autophagic delivery of Golgi components, and hinders Golgi protein degradation. In addition to nutrient stress, TM9SF3 is essential for Golgiphagy induced by monensin, brefeldin A, and glycosylation perturbations. Knockout or LIR mutation of TM9SF3 disrupts protein glycosylation, whereas its overexpression promotes the degradation of aberrantly glycosylated proteins. Notably, TM9SF3 promotes breast cancer cell proliferation, and its high expression correlates with poor patient prognosis. Our findings establish TM9SF3 as a Golgiphagy receptor essential for maintaining Golgi integrity and glycosylation fidelity, and implicate its role in supporting cancer progression.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710280","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":"Renal tubular VMP1 protects against acute kidney injury via modulating autophagy and autophagy-independent pathway.","authors":"Wenwen Yang, Meng Jia, Fenglian Zhou, Mingchao Zhang, Shuang Qu, Caihong Zeng, Xiaodong Zhu, Shouyong Gu, Ji Xuan, Zhihong Liu, Ke Zen","doi":"10.1080/15548627.2025.2533306","DOIUrl":"10.1080/15548627.2025.2533306","url":null,"abstract":"<p><p>Macroautophagy/autophagy activation protects renal proximal tubular epithelial cells (PTECs) against acute kidney injury (AKI) induced by various challenges. The mechanism that regulates autophagy in PTECs, however, remains incompletely understood. Here, we report that VMP1 (vacuole membrane protein 1) plays an essential role in enabling PTECs to maintain high autophagic flow under AKI conditions. VMP1 in PTECs is strongly upregulated in AKI patients but not chronic kidney disease patients. The rapid elevation of VMP1 expression in PTECs during AKI is validated in mouse AKI models induced by cisplatin or ischemia-reperfusion injury (IRI). PTECs-specific <i>vmp1-</i>knockout mice (<i>vmp1-</i>cKO) display more severe renal injuries when challenged with cisplatin or IRI. In line with this, aging <i>vmp1-</i>cKO mice spontaneously develop defective calcium metabolism and display significant tubular damage. In contrast, adenovirus-mediated <i>Vmp1</i> expression in renal tubular rescues IRI or cisplatin-induced renal tubular injury. Mechanistically, the level and distribution pattern of VMP1 are associated with the autophagy markers MAP1LC3/LC3 and SQSTM1, and VMP1 facilitates the formation of renal tubular cell autophagosomes. <i>VMP1</i> deficiency also results in the accumulation of lipid droplets in renal tubular cells. Our studies thus reveal a critical role of VMP1 in protecting against AKI via facilitating tubular cell autophagic flux and lipid metabolism.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144638899","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":"Restricting intracellular <i>Salmonella</i> proliferation by coordinating p-TBK1 mediated mitophagy and xenophagy.","authors":"Jun Li, Yang Yang, Yao Ge, Xinyu Zhang, Haozhen Liu, Yinfeng Chen, Ying Yang, Zhenlong Wu","doi":"10.1080/15548627.2025.2534298","DOIUrl":"10.1080/15548627.2025.2534298","url":null,"abstract":"<p><p>Mitophagy is essential for eliminating dysfunctional mitochondria and is closely implicated in the immune evasion of several pathogens, including <i>S. typhimurium</i>. However, the specific mechanisms regarding the interaction between <i>S. typhimurium</i> and host cells in relation to mitophagy and xenophagy and their contribution to pathogen survival are unclear. Herein, using both <i>in vitro</i> and <i>in vivo</i> systems, we found that <i>S. typhimurium</i> escaped host innate immunity by repressing mitophagy and xenophagy to facilitate its intracellular replication. Moreover, we identified a novel xenophagy modulator, fisetin that could activate mitophagy to restrict intracellular <i>S. typhimurium</i> replication in RAW264.7 and bone marrow-derived macrophages, which was abolished by mitophagy inhibitor Mdivi-1. RNA-Seq transcriptome and metabolomics analysis demonstrated the effectiveness of fisetin in alleviating <i>S. typhimurium</i> infection. Confocal microscopy analysis revealed that fisetin-induced mitophagy promoted xenophagy, whereas inhibiting mitophagy repressed xenophagy and facilitated the survival of <i>S. typhimurium</i>. Our study further demonstrates that fisetin-induced mitophagy requires the recruitment of phosphorylation of TBK1 to mitochondria, which is a protein implicated in mitophagy and xenophagy. Additionally, fisetin improved the body weight loss, relative spleen, kidney, and liver weights, hepatic damage, and <i>S. typhimurium</i> load, all of which were abrogated by Mdivi-1 or Pink1 siRNA treatment in <i>S. typhimurium</i>-infected mice. Collectively, our results suggest that <i>S. typhimurium</i> induces mitochondrial damage whilst inhibiting mitophagy, while fisetin promotes xenophagy and restrains <i>S. typhimurium</i> survival by facilitating Pink1-Parkin mediated mitophagy and p-TBK1 mitochondrial recruitment. Fisetin proves effective as a xenophagy enhancer in reducing intracellular <i>Salmonella</i> burden.<b>Abbreviations</b>: BafA1: bafilomycin A1; BMDM: mouse bone marrow-derived macrophage; CFU: colony-forming units; LAMP2: lysosome-associated membrane protein gene; LC3: microtubule associated protein 1 light chain 3; LDH: Lactate dehydrogenase; Mdivi-1: mitochondrial division inhibitor 1; NDP52: nuclear domain 10 protein 52; OPTN: optineurin; PBS, phosphate buffer saline; Pink1: PTEN-induced putative kinase 1; siRNA: interfering RNA; SQSTM1/p62: sequestosome 1; <i>S. typhimurium</i>: <i>Salmonella enterica serovar typhimurium</i>; T3SS: type III secretion system 1; TBK1: TANK-binding kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-23"},"PeriodicalIF":0.0,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144638900","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":"Taurine ameliorates viral encephalitis by restoring PRKN-mediated mitophagy.","authors":"Xiaowei Song, Yifei Wang, Kai Zheng","doi":"10.1080/15548627.2025.2538767","DOIUrl":"10.1080/15548627.2025.2538767","url":null,"abstract":"<p><p>Mitophagy is a selective type of autophagy that removes damaged mitochondria to maintain mitochondrial homeostasis and regulate the antiviral immune response. Despite increasing evidence that herpes simplex virus type 1 (HSV-1) infection causes mitochondrial damage, the regulatory mechanisms governing mitochondrial homeostasis and its biological implications in the context of HSV-1 infection and viral encephalitis remain unclear. In our recent work, we find that HSV-1 infection causes the accumulation of damaged mitochondria via defective mitophagy <i>in vitro</i> and in brain tissue of mice. The viral proteins ICP34.5 and US11 inhibit the EIF2S (eukaryotic translation initiation factor 2 subunit alpha)-ATF4 (activating transcription factor 4) axis to transcriptionally suppress <i>PRKN/Parkin</i> expression and subsequently impede PRKN-dependent mitophagy. Consequently, modulation of mitophagy significantly affects HSV-1 infection and NFKB/NF-κB-mediated neuroinflammation, as well as the severity of viral encephalitis in mice. Moreover, taurine, a metabolite differentially regulated by HSV-1 infection, transcriptionally promotes PRKN-mediated mitophagy, thereby limiting HSV-1 infection both <i>in vitro</i> and <i>in vivo</i>. This work reveals a protective function of mitophagy in restricting viral encephalitis and highlights the ATF4-PRKN axis as a potential therapeutic approach for the treatment of neurotropic virus-related diseases.<b>Abbreviations:</b> Aβ: amyloid β protein; AD: Alzheimer disease; ATF4: activating transcription factor 4; EIF2AK2/PKR: eukaryotic translation initiation factor 2 alpha kinase 2; EIF2S1: eukaryotic translation initiation factor 2 subunit alpha; HSE: herpes simplex encephalitis; HSV-1: herpes simplex virus type 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700662","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":"Autophagy inhibition in LGALS9-overexpressing nasopharyngeal carcinoma unleashes immune response.","authors":"Clarence Pascual, Daniel J Klionsky","doi":"10.1080/15548627.2025.2534072","DOIUrl":"https://doi.org/10.1080/15548627.2025.2534072","url":null,"abstract":"<p><p>When cells within our bodies begin to exhibit tumor-specific antigens, a specialized group of immune cells, known as immune effector cells, plays a crucial role in mounting both innate and adaptive immune responses. Cancer cells are notorious for developing strategies to hide from, suppress, and manipulate the immune system, collectively known as immune evasion. In the paper by Kam et al. the authors propose that intratumoral cell-associated, as opposed to secreted, LGALS9 (galectin 9) suppresses the activation of cytotoxic T lymphocytes in a macroautophagy/autophagy-dependent manner in nasopharyngeal carcinoma (NPC) cell lines.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692746","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":"PSAT1 inhibits mTORC1 activation by preventing Rag heterodimer formation in lung adenocarcinoma.","authors":"Yuhan Liu, Zhujun Cheng, Jinjin Zhang, Yi Zhang, Tao Zhao, Longhua Sun, Guilan Wen, Tianyu Han, Jianbin Wang","doi":"10.1080/15548627.2025.2535765","DOIUrl":"https://doi.org/10.1080/15548627.2025.2535765","url":null,"abstract":"<p><p>The mechanistic target of rapamycin complex 1 (mTORC1) integrates environmental cues, especially amino acids, to regulate metabolism and ultimately cancer progression. Phosphoserine aminotransferase 1 (PSAT1) is a key enzyme in de novo serine synthesis and its overexpression has been reported to promote oncogenesis in various cancers. Knockdown of PSAT1 inhibits the proliferation and migration of cancer cells. However, our study found an interesting phenomenon that either PSAT1 overexpression or knockout promoted cell proliferation in lung adenocarcinoma (LUAD) which seemed to contradict traditional views. The mechanism was that PSAT1 preferentially bound to GTP-loaded RagB GTPases, preventing the formation of Rag heterodimers. This restricted the lysosome localization of mTORC1 and enhanced the basal level of macroautophagy/autophagy, which promoted the proliferative ability of LUAD cells. PSAT1 knockout resulted in Rag heterodimer formation and mTORC1 activation, promoting protein synthesis and cell proliferation. Additionally, PSAT1 knockout caused a compensatory upregulation of the serine transporter solute carrier family 1 member 5 (SLC1A5), increasing exogenous serine uptake. In conclusion, our study reveals a novel function of PSAT1 in regulation of mTORC1 that affects the proliferation of LUAD cells.<b>Abbreviations</b>: ATG5: autophagy-related 5; BECN1: Beclin 1; CQ: chloroquine; 4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GAP: GTPase-activating protein; GDP: Guanosine nucleotide diphosphate; GTP: Guanosine triphosphate; GTPase: guanosine triphosphatase; LAMP2: lysosome-associated membrane protein 2; LC3: microtubule-associated protein 1 light chain-3, LUAD: lung adenocarcinoma; mTORC1: mechanistic target of rapamycin complex 1; PCC: Pearson's correlation coefficient; PSAT1: Phosphoserine aminotransferase 1; Rag: Ras-related GTP binding; Raptor: regulatory-associated protein of mTOR; S6: ribosomal protein S6; S6K1: substrates S6 kinase 1; SLC1A5: solute carrier family 1 member 5; SSP: serine biosynthetic pathway; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-16"},"PeriodicalIF":0.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700661","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":"Apoptotic bodies derived from human umbilical cord mesenchymal stem cells improve recovery from myocardial infarction in swine.","authors":"Wei Luo, Hao Li, Pengfei Zhang, Hao Cao, Yun Dong, Yanshan Gong, Dongling Zhu, YuanFeng Xin, Zhongmin Liu, Ling Gao","doi":"10.1080/15548627.2025.2536449","DOIUrl":"https://doi.org/10.1080/15548627.2025.2536449","url":null,"abstract":"<p><p>Apoptotic bodies (ABs) are a type of extracellular vesicles (EVs) that could contribute to the paracrine effect of stem cells. However, their potential in treating cardiovascular diseases is largely unexplored. This study investigated the therapeutic effects of ABs derived from human umbilical cord mesenchymal stem cells (MSCs) on cardiac recovery in a porcine model of myocardial infarction (MI). In vitro, ABs reduced apoptosis and cytotoxicity in cardiomyocytes under oxygen and glucose deprivation (OGD) conditions and enhanced the capacity of migration and tube formation in endothelial cells. In vivo, akin to MSCs, administration of ABs improved contractile function, reduced infarct size, and mitigated adverse remodeling in pig hearts with MI, concomitantly with increased cardiomyocyte survival and angiogenesis. These cardioprotective effects were mediated through the regulation of autophagy by activating the adenosine monophosphate - activated protein kinase (AMPK) and transcription factor EB (TFEB) signaling pathways. microRNAs contained in ABs were sequenced, revealing that let-7f-5p was the most abundant. let-7f-5p promoted AMPK phosphorylation by targeting protein phosphatase 2 regulatory subunit B alpha (PPP2R2A) and decreased TFEB phosphorylation by targeting MAP4K3 to regulate autophagy, thereby contributing to the effects of ABs. Overall, these findings indicate that MSC-derived ABs have the potential to be a promising and effective acellular therapeutic option for treating MI.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669070","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":"Activation of endogenous PRKN by structural derepression is linked to increased turnover of the E3 ubiquitin ligase.","authors":"Fabienne C Fiesel, Bernardo A Bustillos, Jens O Watzlawik, Carol X Q Chen, Martin H Berryer, Jiazhen Zhang, Paige K Boneski, Caleb S Hayes, Jenny M Bredenberg, Eric Deneault, Zhipeng You, Narges Abdien, Nathalia Aprahamian, Taylor M Goldsmith, Zahra Baninameh, Liam T Cocker, Haonan Zhang, Matthew S Goldberg, Edward A Fon, Jean-François Trempe, Satpal Virdee, Thomas M Durcan, Wolfdieter Springer","doi":"10.1080/15548627.2025.2531025","DOIUrl":"10.1080/15548627.2025.2531025","url":null,"abstract":"<p><p>Loss-of-function mutations in the <i>PINK1</i> and <i>PRKN</i> genes are the most common cause of early-onset Parkinson disease (PD). The encoded enzymatic pair selectively identifies, labels, and targets damaged mitochondria for degradation via the macroautophagy/autophagy-lysosome system (mitophagy). This pathway is cytoprotective and efforts to activate mitophagy are pursued as therapeutic avenues to combat PD and other neurodegenerative disorders. When mitochondria are damaged, the ubiquitin kinase PINK1 accumulates and recruits PRKN from the cytosol to activate the E3 ubiquitin ligase from its auto-inhibited conformation. We have previously designed several mutations that effectively derepress the structure of PRKN and activate its enzymatic functions <i>in vitro</i>. However, it remained unclear how these PRKN-activating mutations would perform endogenously in cultured neurons or <i>in vivo</i> in the brain. Here, we gene-edited neural progenitor cells and induced pluripotent stem cells to express PRKN-activating mutations in dopaminergic cultures. All tested PRKN-activating mutations indeed enhanced the enzymatic activity of PRKN in the absence of exogenous stress, but their hyperactivity was linked to their own PINK1-dependent degradation. Strikingly, <i>in vivo</i> in a mouse model expressing an equivalent activating mutation, we find the same relationship between PRKN enzymatic activity and protein stability. We conclude that PRKN degradation is the consequence of its structural derepression and enzymatic activation, thus resulting only in a temporary gain of activity. Our findings imply that pharmacological activation of endogenous PRKN will lead to increased turnover and suggest that additional considerations might be necessary to achieve sustained E3 ubiquitin ligase activity for disease treatment.<b>Abbreviations:</b> BSA: bovine serum album, CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECL: electrochemiluminescence; EGF: epidermal growth factor; ELISA: enzyme-linked immunosorbent assay; FGF: fibroblast growth factor; iPSC: induced pluripotent stem cell; KI: knock-in; KO: knockout; MAP2: microtubule associated protein 2; MFN2: mitofusin 2; MSD: Meso Scale Discovery; mt-Keima: mitochondrial targeted Keima; NPC: neural progenitor cell; PD: Parkinson disease; PDH: pyruvate dehydrogenase; p-S65-PRKN: Serine 65 phosphorylated PRKN; p-S65-Ub: Serine 65 phosphorylated ubiquitin; REP: repressor element of PRKN; TH: tyrosine hydroxylase; TX: Triton X-100, Ub: ubiquitin; UBL: ubiquitin-like; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585823","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":"MoOrp-mediated PtdIns4P transportation is essential for autophagy and pathogenicity in <i>Magnaporthe oryzae</i>.","authors":"Jian Wang, Meng-Meng Chen, Hai-Jiao Xu, Yu-Jie Wang, Si-Ru Yang, Ning Liu, Xiao-Lin Chen, You-Liang Peng, Jun Fan","doi":"10.1080/15548627.2025.2531036","DOIUrl":"10.1080/15548627.2025.2531036","url":null,"abstract":"<p><p>Macroautophagy/autophagy is essential to the pathogenicity of <i>Magnaporthe oryzae</i>. Phosphatidylinositol-4-phosphate (PtdIns4P) is a key lipid involved in the autophagy process. Recent studies have shown that the PtdIns4P pool on autophagic membranes is crucial to autophagosome biogenesis and fusion with the vacuole; however, the mechanism regulating the PtdIns4P levels on autophagic membranes is still unclear. Here, we report that two oxysterol-binding protein-related proteins, MoOrp1 and MoOrp2, required for the pathogenicity in <i>M. oryzae</i>, function as PtdIns4P transporters to modulate the autophagy process. We found that simultaneous knockout of <i>MoORP1</i> and <i>MoORP2</i> genes (△<i>Moorp</i>_<i>1-2</i>) led to a range of defects in autophagy-related infection processes, including lipid degradation and autophagic cell death in conidia, generation of appressorial turgor pressure required for host penetration, and growth of infectious hyphae in plant cells. Autophagy flux assays of the △<i>Moorp</i>_<i>1-2</i> strain revealed a prominent deficiency in autophagosome formation and fusion with the vacuole. Molecular analyses showed that both MoOrp1 and MoOrp2 could bind PtdIns4P and be recruited to the autophagosome by interacting with MoAtg8. Disruption of the two <i>MoORP</i> genes impeded the autophagy-induced PtdIns4P accumulation on the autophagosome and vacuolar membrane. Disturbance of the molecular features vital for PtdIns4P-binding activity in MoOrp1 and MoOrp2 abolished their function in autophagy and pathogenicity. Hence, our study uncovers new roles of the Atg8 protein and highlights the significance of the MoOrp-mediated PtdIns4P translocation in regulating autophagy and pathogenicity in <i>M. oryzae.</i><b>Abberivations:</b> Atg: autophagy related; BiFC: bimolecular fluorescence complementation; CHOL: cholesterol; CM: complete medium; CL: cardiolipin; Co-IP: co-immunoprecipitation; DAG: diacylglycerol; FDA: fluorescein diacetate; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; hpi: hours post inoculation; IH: invasive hypha; LDs: lipid droplets; MM-N: minimum medium minus nitrogen; Mo: Magnaporthe oryzae; ORPs: oxysterol-binding protein-related proteins; OSBP: oxysterol-binding protein; ORD: OSBP-related domain; PAS: phagophore assembly site; PA: phosphatidic acid; PS: phosphatidylserine; PE: phosphatidylethanolamine; PC: phosphatidylcholine; PG: phosphatidylglycerol; PtdIns: phosphatidylinositol; PIs: phosphoinositides; PtdIns4Ks: phosphatidylinositol 4-kinases; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns4P: phosphatidylinositol-4-phosphate; PtdIns(3,5)P₂: phosphatidylinositol-3,5-bisphosphate; PtdIns(4,5)P₂: phosphatidylinositol-4,5-bisphosphate; PM: plasma membrane; SM: sphingomyelin; ST: sulfatide; TG: triglyceride; TOR: target of rapamycin; YFP: yellow fluorescent protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585824","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}