Autophagy最新文献

{"title":"ADSL-produced fumarate increases BECN1 dimethylation to promote autophagy and liver tumor growth.","authors":"Lei Wang, Guimei Ji, Yuran Duan, Peixiang Zheng, Zhiqiang Hu, Zheng Wang, Daqian Xu","doi":"10.1080/15548627.2025.2481125","DOIUrl":"10.1080/15548627.2025.2481125","url":null,"abstract":"<p><p>Cancer cells depend on the reprogramming of cell metabolism to constantly adapt metabolically to the tumor microenvironment. ADSL (adenylosuccinate lyase), a rate-limiting enzyme in de novo purine synthesis, is overexpressed in various cancer cells. However, whether ADSL functions in other oncogenic signaling is largely unknown. Here, our recent study shows that ADSL interacts with BECN1 (beclin 1) to regulate macroautophagy/autophagy upon lipid deprivation. Mechanistically, ADSL is phosphorylated at S140 by EIF2AK3/PERK (eukaryotic translation initiation factor 2 alpha kinase 3) in response to lipid deprivation, which enhances the association between ADSL and BECN1. ADSL-produced fumarate reduces the BECN1-associated KDM8 activity, leading to increased BECN1 K117 dimethylation. BECN1 K117 dimethylation inhibits its interaction with BCL2 to initiate autophagy. Targeting the ADSL-BECN1 axis by knock-in mutation or a cell-penetrating peptide inhibits autophagy and blunts liver tumor growth in mice. These findings broaden the physiological significance of ADSL in autophagy and liver tumor development.<b>Abbreviation</b>: α-KG: alpha-ketoglutarate; ADSL: adenylosuccinate lyase; AMP: adenosine monophosphate; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; HCC: hepatocellular carcinoma; KDM8: lysine demethylase 8; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ULK1: unc-51 like autophagy activating kinase 1; WIPI2: WD repeat domain, phosphoinositide interacting 2.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1616-1617"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660088","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":"Lysosomal quality control Review.","authors":"Danielle Henn, Xi Yang, Ming Li","doi":"10.1080/15548627.2025.2469206","DOIUrl":"10.1080/15548627.2025.2469206","url":null,"abstract":"<p><p>Healthy cells need functional lysosomes to degrade cargo delivered by autophagy and endocytosis. Defective lysosomes can lead to severe conditions such as lysosomal storage diseases (LSDs) and neurodegeneration. To maintain lysosome integrity and functionality, cells have evolved multiple quality control pathways corresponding to different types of stress and damage. These can be divided into five levels: regulation, reformation, repair, removal, and replacement. The different levels of lysosome quality control often work together to maintain the integrity of the lysosomal network. This review summarizes the different quality control pathways and discusses the less-studied area of lysosome membrane protein regulation and degradation, highlighting key unanswered questions in the field.<b>Abbreviation</b>: ALR: autophagic lysosome reformation; CASM: conjugation of ATG8 to single membranes: ER: endoplasmic reticulum; ESCRT: endosomal sorting complexes required for transport; ILF: intralumenal fragment; LSD: lysosomal storage disease; LYTL: lysosomal tubulation/sorting driven by LRRK2; PITT: phosphoinositide-initiated membrane tethering and lipid transport; PE: phosphatidylethanolamine; PLR: phagocytic lysosome reformation; PS: phosphatidylserine; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns4P: phosphatidylinositol-4-phosphate; PtdIns(4,5)P₂: phosphatidylinositol-4,5-bisphosphate; V-ATPase: vacuolar-type H⁺-translocating ATPase.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1413-1432"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451314","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":"Establishment of a yeast essential protein conditional-degradation library and screening for autophagy-regulating genes.","authors":"Yi Zhang, Yingcong Chen, Choufei Wu, Zhengyi Cai, Weijing Yao, Huan Yang, Juan Song, Xiankuan Xie, Liqin Zhang, Cong Yi","doi":"10.1080/15548627.2025.2469189","DOIUrl":"10.1080/15548627.2025.2469189","url":null,"abstract":"<p><p>Macroautophagy/autophagy is an evolutionarily conserved intracellular degradation pathway that relies on vacuoles or lysosomes. Over 40 <i>ATG</i> genes have been identified in yeast cells as participants in various types of autophagy, although these genes are non-essential. While some essential genes involved in autophagy have been identified using temperature-sensitive yeast strains, systematic research on essential genes in autophagy remains lacking. To address this, we established an essential protein conditional degradation library using the auxin-inducible degron (AID) system. By introducing the GFP-Atg8 plasmid, we identified 29 essential yeast genes involved in autophagy, 19 of which had not been previously recognized. In summary, the yeast essential protein conditional degradation library we constructed will serve as a valuable resource for systematically investigating the roles of essential genes in autophagy and other biological functions.<b>Abbreviation:</b> AID: auxin-inducible degron; ALP: alkaline phosphatase; ATG: autophagy related; CSG: constitutive slow growth; DAmP: Decreased Abundance by mRNA Perturbation; GFP: green fluorescent protein; MMS: methyl methanesulfonate; ORF: open reading frame; PAS: phagophore assembly site; PCR: polymerase chain reaction; SD-G: glucose starvation medium; SD-N: nitrogen starvation medium; TOR: target of rapamycin kinase; YGRC: yeast genetic resource center; YPD: yeast extract peptone dextrose.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1578-1590"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484987","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":"Visualizing bulk autophagy <i>in vivo</i> by tagging endogenous LC3B.","authors":"Xiukui Gao, Yue Xiong, Hangbin Ma, Hao Zhou, Wei Liu, Qiming Sun","doi":"10.1080/15548627.2025.2457910","DOIUrl":"10.1080/15548627.2025.2457910","url":null,"abstract":"<p><p>Macroautophagy/autophagy plays a crucial role in maintaining cellular and organismal health, making the measurement of autophagy flux <i>in vivo</i> essential for its study. Current tools often depend on the overexpression of autophagy probes. In this study, we developed a knock-in mouse model, termed tfLC3-KI, by inserting a tandem fluorescent tag coding sequence into the native <i>Map1lc3b</i> gene locus. We found that tfLC3-KI mice exhibit optimal expression of mRFP-eGFP-LC3B, allowing for convenient measurement of autophagic structures and flux at single-cell resolution, both <i>in vivo</i> and in primary cell cultures. Additionally, we compared autophagy in neurons and glial cells across various brain regions between tfLC3-KI mice and CAG-tfLC3 mice, the latter overexpressing the probe under the strong CMV promoter. Finally, we used tfLC3-KI mice to map the spatial and temporal dynamics of basal autophagy activity in the reproductive system. Our findings highlight the value of the tfLC3-KI mouse model for investigating autophagy flux <i>in vivo</i> and demonstrate the feasibility of tagging endogenous proteins to visualize autophagic structures and flux in both bulk and selective autophagy research <i>in vivo</i>.<b>Abbreviation</b>: BafA₁: bafilomycin A₁; CQ: chloroquine; EBSS: Earle's balanced salt solution; Es: elongating spermatids; HPF: hippocampalformation; HY: hypothalamus; LCs: leydig cells; OLF: olfactory areas; PepA: pepstatin A; Rs: round spermatids; SCs: sertoli cells; Spc: spermatocytes; Spg: spermatogonia; tfLC3: tandem fluorescently tagged mRFP-eGFP-LC3; TH: thalamus.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1591-1607"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426749","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":"Histone lactylation stimulated upregulation of PSMD14 alleviates neuron PANoptosis through deubiquitinating PKM2 to activate PINK1-mediated mitophagy after traumatic brain injury.","authors":"Lei Xu, Yangfan Ye, Wei Gu, Xiao Xu, Nuo Chen, Liuchao Zhang, Wanzhi Cai, Jingming Hu, Tian Wang, Honglu Chao, Yiming Tu, Jing Ji","doi":"10.1080/15548627.2025.2471633","DOIUrl":"10.1080/15548627.2025.2471633","url":null,"abstract":"<p><p>Alleviating the multiple types of programmed neuronal death caused by mechanical injury has been an impetus for designing neuro-therapeutical approaches after traumatic brain injury (TBI). The aim of this study was to elucidate the potential role of PSMD14 (proteasome 26S subunit, non-ATPase 14) in neuron death and the specific mechanism through which it improves prognosis of TBI patients. Here, we identified differential expression of the PSMD14 protein between the controlled cortical impact (CCI) and sham mouse groups by LC-MS proteomic analysis and found that PSMD14 was significantly upregulated in neurons after brain injury by qPCR and western blot. PSMD14 suppressed stretch-induced neuron PANoptosis and improved motor ability and learning performance after CCI in vivo. Mechanistically, PSMD14 improved PINK1 phosphorylation levels at Thr257 and activated PINK1-mediated mitophagy by deubiquitinating PKM/PKM2 (pyruvate kinase M1/2) to maintain PKM protein stability. PSMD14-induced mitophagy promoted mitochondrial homeostasis to reduced ROS production, and ultimately inhibited the neuron PANoptosis. The upregulation of neuronal PSMD14 after TBI was due to the increase of histone lactation modification level and lactate treatment alleviated neuron PANoptosis via increasing PSMD14 expression. Our findings suggest that PSMD14 could be a potential therapeutic approach for improving the prognosis of TBI patients.<b>Abbreviations:</b> CCI: controlled cortical impact; CQ: chloroquine; DUBs: deubiquitinating enzymes; H3K18la: H3 lysine 18 lactylation; IB: immunoblot; IHC: immunohistochemistry; IP: immunoprecipitation; MLKL: mixed lineage kinase domain like pseudokinase; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; PKM/PKM2: pyruvate kinase M1/2; PSMD14: proteasome 26S subunit, non-ATPase 14; ROS: reactive oxygen species; RIPK1: receptor interacting serine/threonine kinase 1; RIPK3: receptor interacting serine/threonine kinase 3; TBI: traumatic brain injury.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1473-1491"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506722","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":"Cleavage of the selective autophagy receptor NBR1 by the PDCoV main protease NSP5 impairs autophagic degradation of the viral envelope protein.","authors":"Ke Li, Dong Chen, Kangli Zhao, Dan Liu, Dongni Kong, Yu Sun, Aohan Guan, Peng Zhou, Hui Jin, Anan Jongkaewwattana, Sizhu Suolang, Dang Wang, Hongbo Zhou, Rui Luo","doi":"10.1080/15548627.2025.2474576","DOIUrl":"10.1080/15548627.2025.2474576","url":null,"abstract":"<p><p>Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus that causes severe diarrhea in neonatal piglets worldwide and presents a significant public health threat due to its potential for cross-species transmission. Selective macroautophagy/autophagy, mediated by autophagy receptors such as NBR1 (NBR1 autophagy cargo receptor), plays a key role in restricting viral infection and modulating the host immune response. In this study, we revealed that overexpression of NBR1 inhibits PDCoV replication, while its knockdown increases viral titers. Further analysis demonstrated that NBR1 interacts with the PDCoV envelope (E) protein independently of ubiquitination, directing it to phagophores for autophagic degradation to limit viral proliferation. To counteract this defense, PDCoV 3C-like protease, encoded by NSP5, cleaves porcine NBR1 at glutamine 353 (Q353), impairing its selective autophagy function and antiviral activity. Additionally, we demonstrated that NSP5 proteases from other coronaviruses including PEDV, TGEV, and SARS-CoV-2 also cleave NBR1 at the same site, suggesting that coronaviruses employ a conserved strategy of NSP5-mediated cleavage of NBR1 to evade host antiviral responses and facilitate infection. Overall, our study underscores the importance of NBR1-mediated selective autophagy in the host's defense against PDCoV and reveals a strategy by which PDCoV evades autophagic mechanisms to promote successful infection.<b>Abbreviation</b>: Cas9: CRISPR-associated protein 9; CC1: coiled-coil 1; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; GFP: green fluorescent protein; IFA: indirect immunofluorescence assay; KO: knockout; LIR: MAP1LC3/LC3-interacting region; mAb: monoclonal antibody; NBR1: NBR1 autophagy cargo receptor; NBR1-C: C-terminal fragment of NBR1; NBR1-N: N-terminal fragment of NBR1; OPTN: optineurin; pAb: polyclonal antibody; PB1: Phox/BEM1 domain; PDCoV: porcine deltacoronavirus; PEDV: porcine epidemic diarrhea virus; Q353A: a NBR1 construct with the glutamine (Q) residue at position 353 replaced with glutamic acid (A); SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SQSTM1: sequestosome 1; TCID₅₀: 50% tissue culture infective dose; TGEV: porcine transmissible gastroenteritis virus; UBA: ubiquitin-associated domain; Ub: ubiquitin; WT: wild type; ZZ: ZZ-type zinc finger domain.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1507-1522"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569281","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":"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":"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":"1523-1543"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665644","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":"Mammalian nucleophagy: process and function.","authors":"Fujian Ji, Enyong Dai, Rui Kang, Daniel J Klionsky, Tong Liu, Yu Hu, Daolin Tang, Kun Zhu","doi":"10.1080/15548627.2025.2455158","DOIUrl":"10.1080/15548627.2025.2455158","url":null,"abstract":"<p><p>The nucleus is a highly specialized organelle that houses the cell's genetic material and regulates key cellular activities, including growth, metabolism, protein synthesis, and cell division. Its structure and function are tightly regulated by multiple mechanisms to ensure cellular integrity and genomic stability. Increasing evidence suggests that nucleophagy, a selective form of autophagy that targets nuclear components, plays a critical role in preserving nuclear integrity by clearing dysfunctional nuclear materials such as nuclear proteins (lamins, SIRT1, and histones), DNA-protein crosslinks, micronuclei, and chromatin fragments. Impaired nucleophagy has been implicated in aging and various pathological conditions, including cancer, neurodegeneration, autoimmune disorders, and neurological injury. In this review, we focus on nucleophagy in mammalian cells, discussing its mechanisms, regulation, and cargo selection, as well as evaluating its therapeutic potential in promoting human health and mitigating disease.<b>Abbreviations</b>: 5-FU: 5-fluorouracil; AMPK, AMP-activated protein kinase; ATG, autophagy related; CMA, chaperone-mediated autophagy; DRPLA: dentatorubral-pallidoluysian atrophy; ER, endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; HOPS, homotypic fusion and vacuole protein sorting; LIR: LC3-interacting region; MEFs: mouse embryonic fibroblasts; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; PCa: prostate cancer; PE: phosphatidylethanolamine; PI3K, phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; rRNA: ribosomal RNA; SCI: spinal cord injury; SCLC: small cell lung cancer; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SupraT: supraphysiological levels of testosterone; TOP1cc: TOP1 cleavage complexes.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1396-1412"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018074","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":"Cancer-associated mutations in autophagy-related proteins analyzed in yeast and human cells.","authors":"Yuchen Lei, Louise Uoselis, Dimitra Dialynaki, Ying Yang, Michael Lazarou, Daniel J Klionsky","doi":"10.1080/15548627.2025.2471142","DOIUrl":"10.1080/15548627.2025.2471142","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a conserved process among eukaryotes and is essential to maintain cell homeostasis; the dysregulation of autophagy has been linked with multiple human diseases, including cancer. However, not many studies have focused on the cancer-related mutations in ATG (autophagy related) proteins, which are likely to affect the protein function, influence autophagy activity and further contribute to the progression of the disease. In this study, we focused on the four ATG4 isoforms, which have a higher mutation frequency compared with the other core ATG proteins (i.e. those involved in autophagosome formation). We first studied the mutations in conserved residues and characterized one cancer-associated mutation that significantly impairs protein function and autophagy activity. Extending the study, we determined a region around the mutant residue to be essential for protein function, which had yet to be examined in previous studies. In addition, we created a yeast system expressing the human ATG4B protein to study mutations in the residues that are not conserved from human to yeast. Using this yeast model, we identified six cancer-associated mutations affecting autophagy. The effects of these mutations were further tested in mammalian cells using a quadruple <i>ATG4</i> gene knockout cell line. Our study proves the principle of using human disease-associated mutations to study Atg proteins in yeast and generates a yeast tool that is helpful for a rapid screen of mutations to determine the autophagy phenotype, providing a new perspective in studying autophagy and its relation with cancer.<b>Abbreviations:</b> 4KO: <i>ATG4</i> tetra knockout; ATG: autophagy related; BafA1: bafilomycin A₁; GFP: green fluorescent protein; LC3-II: PE-conjugated form of LC3B; ORF: open reading frame; PE: phosphatidylethanolamine; RFP: red fluorescent protein; SEP: superecliptic pHluorin; Ubl: ubiquitin-like; UCEC: uterine corpus endometrial carcinoma.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1456-1472"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525496","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":"Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion.","authors":"Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Gary Shangguan, Joseph M Wider, Maik Hüttemann, Thomas H Sanderson","doi":"10.1080/15548627.2025.2472586","DOIUrl":"10.1080/15548627.2025.2472586","url":null,"abstract":"<p><p>Mitochondrial damage and dysfunction are hallmarks of neuronal injury during cerebral ischemia-reperfusion (I/R). Critical mitochondrial functions including energy production and cell signaling are perturbed during I/R, often exacerbating damage and contributing to secondary injury. The integrity of the mitochondrial proteome is essential for efficient function. Mitochondrial proteostasis is mediated by the cooperative forces of mitophagy and intramitochondrial proteolysis. The aim of this study was to elucidate the patterns of mitochondrial protein dynamics and their key regulators during an <i>in vitro</i> model of neuronal I/R injury. Utilizing the MitoTimer reporter, we quantified mitochondrial protein oxidation and turnover during I/R injury, highlighting a key point at 2 h reoxygenation for aged/oxidized protein turnover. This turnover was found to be mediated by both LONP1-dependent proteolysis and PRKN/parkin-dependent mitophagy. Additionally, the proteostatic response of neuronal mitochondria is influenced by both mitochondrial fusion and fission machinery. Our findings highlight the involvement of both mitophagy and intramitochondrial proteolysis in the response to I/R injury.<b>Abbreviations</b>: cKO: conditional knockout; CLPP: caseinolytic mitochondrial matrix peptidase proteolytic subunit; DIV: days <i>in vitro</i>; DNM1L/DRP1: dynamin 1 like; ETC: electron transport chain; hR: hours after reoxygenation; I/R: ischemia-reperfusion; LONP1: lon peptidase 1, mitochondrial; mtUPR: mitochondrial unfolded protein response; OGD: oxygen glucose deprivation; OGD/R: oxygen glucose deprivation and reoxygenation; OPA1: OPA1 mitochondrial dynamin like GTPase; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROI: region of interest; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1492-1506"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525500","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}