Autophagy最新文献

{"title":"ATG16L1 WD domain and linker regulates lipid trafficking to maintain plasma membrane integrity to limit influenza virus infection.","authors":"Benjamin Bone, Luke Griffith, Matthew Jefferson, Yohei Yamauchi, Thomas Wileman, Penny P Powell","doi":"10.1080/15548627.2025.2482516","DOIUrl":"https://doi.org/10.1080/15548627.2025.2482516","url":null,"abstract":"<p><p>The non-canonical functions of autophagy protein ATG16L1 are dependent on a C-terminal WD domain. Recent studies show that the WD domain is required for conjugation of LC3 to single membranes during endocytosis and phagocytosis, where it is thought to promote fusion with lysosomes. Studies in cells lacking the WD domain suggest additional roles in the regulation of cytokine receptor recycling and plasma membrane repair. The WD domain also protects mice against lethal influenza virus <i>in vivo</i>. Here, analysis of mice lacking the WD domain (ΔWD) shows enrichment of cholesterol in brain tissue suggesting a role for the WD domain in cholesterol transport. Brain tissue and cells from ΔWD mice showed reduced cholesterol and phosphatidylserine (PS) in the plasma membrane. Cells from ΔWD mice also showed an intracellular accumulation of cholesterol predominantly in late endosomes. Infection studies using IAV suggest that the loss of cholesterol and PS from the plasma membrane in cells from ΔWD mice results in increased endocytosis and nuclear delivery of IAV, as well as increased <i>Ifnb</i>/<i>Ifnβ</i> and <i>Isg15</i> gene expression. Upregulation of <i>Il6</i>, <i>Ifnb</i> and <i>Isg15</i> mRNA were observed in \"ex vivo\" precision cut lung slices from ΔWD mice both at rest and in response to IAV infection. Overall, we present evidence that regulation of lipid transport by the WD domain of ATG16L1 May have downstream implications in attenuating viral infection and limiting lethal cytokine signaling.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722982","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":"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":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652612","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 TBK1-SCF^FBXO3-TMEM192-TAX1BP1 axis: a novel regulatory mechanism for lysophagy.","authors":"Na Yeon Park, Dong-Hyung Cho","doi":"10.1080/15548627.2025.2479669","DOIUrl":"10.1080/15548627.2025.2479669","url":null,"abstract":"<p><p>Lysophagy, the selective macroautophagic/autophagic clearance of damaged lysosomes, is a critical mechanism for maintaining cellular homeostasis. Our recent study identified a novel regulatory axis involving TBK1, SCF^FBXO3, TMEM192, and TAX1BP1 that orchestrates lysophagic flux following lysosomal damage. We demonstrated that TBK1-dependent phosphorylation of FBXO3 facilitates its interaction with TMEM192, promoting its ubiquitination and subsequent recognition by the autophagy receptor TAX1BP1. Perturbing this pathway significantly reduces lysophagic flux and results in accumulation of damaged lysosomes. These findings establish a previously unrecognized mechanistic link between ubiquitination, receptor recruitment, and lysophagic degradation, broadening our understanding of lysosomal quality control.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626860","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":"PTK6 drives HNRNPH1 phase separation to activate autophagy and suppress apoptosis in colorectal cancer.","authors":"Bingyuan Chen, Bowen Liu, Junnan Chen, Wenjing Li, Ning Ma, Jianquan Liu, Ruizhi Fan, Qihang Hu, Hu Song, Yixin Xu, Tao Jiang, Jun Song","doi":"10.1080/15548627.2025.2481001","DOIUrl":"10.1080/15548627.2025.2481001","url":null,"abstract":"<p><p>Macroautophagy/autophagy is the principal mechanism that mediates the delivery of various cellular cargoes to lysosomes for degradation and recycling, and has been reported to play a crucial role in colorectal cancer (CRC) pathogenesis and progression. Targeting autophagy may be a promising therapeutic strategy for CRC. However, the specific functions and potential mechanisms of autophagy in CRC remain unclear. In the present study, we discovered that PTK6 (protein tyrosine kinase 6) could activate autophagy and inhibit CRC apoptosis. PTK6 physically interacted with HNRNPH1 and mediated tyrosine phosphorylation at Y210 of HNRNPH1, which promoted the latter's liquid-liquid phase separation (LLPS). Furthermore, LLPS of HNRNPH1 formed biomolecular condensates and triggered splicing-switching of the <i>NBR1</i> exon 10 inclusion transcript, thereby activating autophagy and suppressing apoptosis of CRC. Additionally, PDO and CDX models indicated that tilfrinib, an inhibitor targeting PTK6, could inhibit CRC growth. Overall, our findings reveal the novel PTK6-HNRNPH1-NBR1 regulatory autophagy axis and provide a potential therapy target for CRC.<b>Abbreviation</b>: 1,6HD: 1,6-hexanediol, CQ: chloroquine, CRC: colorectal cancer, DFS: disease-free survival, FRAP: fluorescence recovery afterphotobleaching, GSEA: Gene Set Enrichment Analysis, GTEx: Genotype-Tissue Expression, HNRNPH1: heterogeneous nuclearribonucleoprotein H1, IDRs: intrinsically disordered regions, IHC: immunohistochemical, KEGG: Kyoto Encyclopedia of Genes and Genomes,LLPS: liquid-liquid phase separation, NBR1: NBR1 autophagy cargoreceptor, OS: overall survival, PDO: patient-derivedorganoid, PTK6: protein tyrosine kinase 6, PTMs: post-translationalmodifications, SE: skipped exon, TCGA: The Cancer Genome Atlas, TEM: transmission electron microscopy, TMA: tissue microarray, TyrKc: tyrosine kinase catalytic.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660093","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":"HMBOX1 reverses autophagy mediated 5-fluorouracil resistance through promoting HACE1-induced ubiquitination and degradation of ATG5 in colorectal cancer.","authors":"Yan Gao, Shenao Fu, Yinghui Peng, Yulai Zhou, Jiang Zhu, Xiangyang Zhang, Changjing Cai, Ying Han, Hong Shen, Shan Zeng","doi":"10.1080/15548627.2025.2477443","DOIUrl":"https://doi.org/10.1080/15548627.2025.2477443","url":null,"abstract":"<p><p>Chemotherapy remains the primary treatment for unresectable or advanced postoperative colorectal cancers. However, its effectiveness is compromised by chemoresistance, which adversely affects patient outcomes. Dysregulated macroautophagy/autophagy is a proposed mechanism behind this resistance, with ubiquitination playing a key regulatory role. In this study, we identify the transcription factor HMBOX1 (homeobox containing 1) as a critical regulator of chemoresistance in colorectal cancer. RNA sequencing revealed that <i>HMBOX1</i> is downregulated in drug-resistant colorectal cancer cells and tissues, with its low expression linked to poor prognosis. An integrated analysis of genes associated with autophagy and 5-fluorouracil (5-FU) resistance was conducted, verified in the colorectal cancer tissues of patients by single-cell RNA sequencing and immunostaining. Mass-spectrometry-based proteomics and RNA sequencing were used to elucidate the underlying molecular mechanisms. Functionally, upregulation of HMBOX1 enhances the sensitivity of colorectal cancer cells to the first-line treatment with 5-FU by inhibiting autophagy. Mechanistically, HMBOX1 promotes the transcription of the E3 ubiquitin ligase HACE1, which in turn enhances ATG5 K63-ubiquitination and subsequent proteasome-mediated degradation. This results in decreased ATG5 levels, inhibiting autophagy and thus reducing 5-FU resistance in colorectal cancer cells both <i>in vitro</i> and <i>in vivo</i>. Furthermore, we confirm that HMBOX1 expression positively correlates with HACE1 expression and inversely correlates with autophagy levels in clinical colorectal cancer tissues. Our findings suggest that HMBOX1 downregulation drives 5-FU resistance through autophagy enhancement in colorectal cancer, highlighting HMBOX1 as a potential target for improving chemosensitivity and patient prognosis.<b>Abbreviation</b>: 3-MA: 3-methyladenine; 5-FU: 5-fluorouracil; ATG: autophagy related; CASP3: caspase 3; C-CASP3: cleaved caspase 3; C-PARP: cleaved PARP; CCK8: cell counting kit-8; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CNV: copy number variation; co-IP: co-immunoprecipitation; COAD: colorectal adenocarcinoma; CQ: chloroquine; CRC: colorectal cancer; CR: complete response; FHC: fetal human colon; GEO: Gene Expression Omnibus; HACE1: HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1; HMBOX1: homeobox containing 1; IHC: immunohistochemistry; LC-MS/MS: liquid chromatography-tandem mass spectrometry; mIHC: multiplexed immunohistochemistry; MUT: mutant; NC: negative control; OS: overall survival; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PFS: progression-free survival; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TF: translation factor; USP22: ubiquitin specific peptidase 22; WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-22"},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694763","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 mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.","authors":"Jared T Field, Donald Chapman, Yan Hai, Saeid Ghavami, Adrian R West, Berkay Ozerklig, Ayesha Saleem, Julia Kline, Asher A Mendelson, Jason Kindrachuk, Barbara Triggs-Raine, Joseph W Gordon","doi":"10.1080/15548627.2025.2476872","DOIUrl":"10.1080/15548627.2025.2476872","url":null,"abstract":"<p><p>Mitochondrial quality control is critical in muscle to ensure contractile and metabolic function. BNIP3L/Nix is a BCL2 member, a mitophagy receptor, and has been implicated in muscle atrophy. Human genome-wide association studies (GWAS) suggest altered BNIP3L expression could predispose to mitochondrial disease. To investigate BNIP3L function, we generated a muscle-specific knockout model. <i>bnip3l</i> knockout mice displayed a ragged-red fiber phenotype, along with accumulation of mitochondria and endo/sarcoplasmic reticulum with altered morphology. Intriguingly, <i>bnip3l</i> knockout mice were more insulin sensitive with a corresponding increase in glycogen-rich muscle fibers. Kinome and gene expression analyses revealed that <i>bnip3l</i> knockout impairs NFAT and MSTN (myostatin) signaling, with alterations in muscle fiber-type and evidence of regeneration. Mechanistic experiments demonstrated that BNIP3L modulates mitophagy, along with reticulophagy leading to altered nuclear calcium signaling. Collectively, these observations identify novel roles for BNIP3L coordinating selective autophagy, oxidative gene expression, and signaling pathways that maintain the muscle phenotype.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588573","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":"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":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626688","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":"ATG2A-WDR45/WIPI4-ATG9A complex-mediated lipid transfer and equilibration during autophagosome formation.","authors":"Yang Wang, Goran Stjepanovic","doi":"10.1080/15548627.2025.2473388","DOIUrl":"https://doi.org/10.1080/15548627.2025.2473388","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a highly conserved cellular process, spanning from yeast to humans, and plays a vital role in maintaining cellular homeostasis. Dysregulation of autophagy has been linked to a wide range of diseases. A hallmark of autophagy is the formation of double-membrane vesicles called autophagosomes. Autophagosome biogenesis requires a large number of phospholipids, with the endoplasmic reticulum (ER) being the main lipid source. The ATG2A-WDR45/WIPI4-ATG9A complex serves as the core machinery responsible for lipid transfer and equilibration during this process. In our recent study, we resolved the cryo-electron microscopy (cryo-EM) structures of the ATG2A-WDR45/WIPI4 and ATG2A-WDR45/WIPI4-ATG9A complexes, providing critical insights into their architecture and function. Additionally, molecular dynamics simulations were employed to investigate the mechanism by which ATG2A mediates lipid extraction from donor membranes. Our findings offer structural and mechanistic insights into the spatially coupled processes of lipid transfer and re-equilibration, which are essential for phagophore membrane expansion.<b>Abbreviation:</b> ATG: autophagy related; ATG2A: autophagy related 2A; ATG2A[NR]: ATG2A N-terminal region; ATG9A: autophagy related 9A; cryo-EM: cryo-electron microscopy; cryo-ET: cryo-electron tomography; ER: endoplasmic reticulum; PtdIns3P: phosphatidylinositol-3-phosphate; <i>Sp</i>Atg2[NR]: <i>Schizosaccharomyces pombe</i> Atg2 N-terminal region; SUVs: small unilamellar vesicles; TGN: trans-Golgi network; TMEM41B: transmembrane protein 41B; VMP1: vacuole membrane protein 1; WDR45/WIPI4: WD repeat domain 45.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675094","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":"Microplastics exacerbate ferroptosis via mitochondrial reactive oxygen species-mediated autophagy in chronic obstructive pulmonary disease.","authors":"Yuan Yuan Wei, Ting Ting Chen, Da Wei Zhang, Ying Zhang, Fang Li, Yi Chuan Ding, Ming Yu Wang, Ling Zhang, Ke Gong Chen, Guang He Fei","doi":"10.1080/15548627.2025.2481126","DOIUrl":"https://doi.org/10.1080/15548627.2025.2481126","url":null,"abstract":"<p><p>Microplastics (MPs) induce mitochondrial dysfunction and iron accumulation, contributing to mitochondrial macroautophagy/autophagy and ferroptosis, which has increased susceptibility to the exacerbation of chronic obstructive pulmonary disease (COPD); however, the underlying mechanism remains unclear. We demonstrated that MPs intensified inflammation in COPD by enhancing autophagy-dependent ferroptosis (ADF) in vitro and in vivo. In the lung tissues of patients with COPD, the concentrations of MPs, especially polystyrene microplastics (PS-MPs), were significantly higher than that of the control group, as detected by pyrolysis gas chromatography mass spectrometry (Py-GCMS), with increased iron accumulation. The exposure to PS-MPs, 2 μm in size, resulted in their being deposited in the lungs of COPD model mice detected by optical in vivo imaging, and observed in bronchial epithelial cells traced by GFP-labeled PS-MPs. There were mitochondrial impairments accompanied by mitochondrial reactive oxygen species (mito-ROS) overproduction and significantly increased levels of lysosome biogenesis and acidification in pDHBE cells with PS-MP stimulation, triggering occurrence of ferritinophagy and enhancing ADF in COPD, which triggered acute exacerbation of COPD (AECOPD). Reestablishing autophagy-dependent ferroptosis via mitochondria-specific ROS scavenging or ferroptosis inhibition alleviated excessive inflammation and ameliorated AECOPD induced by PS-MPs. Collectively, our data initially revealed that MPs exacerbate ferroptosis via mito-ROS-mediated autophagy in COPD, which sheds light on further hazard assessments of MPs on human respiratory health and potential therapeutic agents for patients with COPD.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671916","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":"Kit-mediated autophagy suppression driven by a viral oncoprotein emerges as a crucial survival mechanism in Merkel cell carcinoma.","authors":"Hao Shi, Yajie Yang, Jiwei Gao, Satendra Kumar, Hong Xie, Ziqing Chen, Jiawen Lyu, Harri Sihto, Virve Koljonen, Silvia Vega-Rubin-de-Celis, Vladana Vukojevic, Filip Farnebo, Viveca Björnhagen, Anders Höög, C Christofer Juhlin, Linkiat Lee, Malin Wickström, Jürgen C Becker, John Inge Johnsen, Catharina Larsson, Weng-Onn Lui","doi":"10.1080/15548627.2025.2477385","DOIUrl":"https://doi.org/10.1080/15548627.2025.2477385","url":null,"abstract":"<p><p>The KIT/c-KIT proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin cancer commonly caused by Merkel cell polyomavirus (MCPyV). Here, we demonstrated that truncated MCPyV-encoded large T-antigen (LT) suppressed macroautophagy/autophagy by stabilizing and sequestering KIT in the paranuclear compartment via binding VPS39. KIT engaged with phosphorylated BECN1, thereby enhancing its association with BCL2 while diminishing its interaction with the PIK3C3 complex. This process ultimately resulted in the suppression of autophagy. Depletion of KIT triggered both autophagy and apoptosis, and decreased LT expression. Conversely, blocking autophagy in KIT-depleted cells restored LT levels and rescued apoptosis. Additionally, stimulating autophagy efficiently increased cell death and inhibited tumor growth of MCC xenografts in mice. These insights into the interplay between MCPyV LT and autophagy regulation reveal important mechanisms by which viral oncoproteins are essential for MCC cell viability. Thus, autophagy-inducing agents represent a therapeutic strategy in advanced MCPyV-associated MCC.<b>Abbreviation</b>: 3-MA, 3-methyladenine; AL, autolysosome; AP, autophagosome; Baf-A1, bafilomycin A₁; BARA, β-α repeated autophagy specific domain; BH3, BCL2 homology 3 domain; CCD, coiled-coil domain; CHX, cycloheximide; Co-IP, co-immunoprecipitation; CQ, chloroquine; CTR, control; DAPI, 4',6-diamidino-2-phenylindole; EBSS, Earle's balanced salt solution; ECD, evolutionarily conserved domain; EEE, three-tyrosine phosphomimetic mutations Y229E Y233E Y352E; ER, endoplasmic reticulum; FFF, three-tyrosine non-phosphomimetic mutations; FFPE, formalin-fixed paraffin-embedded; FL, full-length; GIST, gastrointestinal stromal tumor; IB, immunoblotting; IHC, immunohistochemistry; KIT-HEK293, KIT stably expressing HEK293 cells; KRT20/CK20, keratin 20; LT, large T-antigen; LT339, MCPyV truncated LT antigen; LTco, codon-optimized MCPyV LT antigen; MCC, Merkel cell carcinoma; MCPyV^-, MCPyV-negative; MCPyV, Merkel cell polyomavirus; MCPyV⁺, MCPyV-positive; PARP1, poly(ADP-ribose) polymerase 1; PCI, pan-caspase inhibitor; PI, propidium iodide; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; RB1, RB transcriptional corepressor 1; RTKs, receptor tyrosine kinases; KITLG/SCF, KIT ligand; sT, small T-antigen; sTco, codon-optimized MCPyV sT antigen; T-B, Tat-BECN1; T-S, Tat-scrambled; TEM, transmission electron microscopy.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665644","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}