Autophagy最新文献

{"title":"Mitochondrial protein nmd regulates lipophagy and general autophagy during development.","authors":"Wei Wang, Xufeng Wang, Xiaoqi Zhou, Lu Jiang, Weina Shang, Liquan Wang, Chao Tong","doi":"10.1080/15548627.2025.2522124","DOIUrl":"10.1080/15548627.2025.2522124","url":null,"abstract":"<p><p>Lipophagy engulfs lipid droplets and delivers them to lysosomes for degradation. We found that lipophagy levels were low in most fly tissues, except for the prothoracic gland (PG) during larval development. Therefore, we performed a small-scale screening in the PG to identify regulators of lipophagy. We discovered that the loss of <i>nmd</i>, a gene encoding a mitochondrial AAA-ATPase, led to developmental failure and reduced lipophagy in the PG. Further studies indicated that <i>nmd</i> was not only required for lipophagy but also essential for general macroautophagy/autophagy in both PG and fat body tissues. Autophagy was induced but blocked at the autophagosome-lysosome fusion stage upon nmd reduction. Additionally, nmd interacted with mitochondrial protein import machinery, such as Tom20, Tom40, and the import cargo, such as Idh. Loss of <i>nmd</i> decreased protein import into mitochondria. Similar to the loss of <i>nmd</i>, reduction of Tom20 or Tom40 also resulted in reduced lipophagy in the PG. In adult flies, reducing <i>nmd</i> expression in the eyes caused lipid droplet accumulation and severe degeneration during aging. Overexpression of bmm, a triglyceride lipase, reduced lipid droplets in the eye but did not rescue the eye degeneration caused by the reduction of <i>nmd</i>.<b>Abbreviation</b>: ATAD1: ATPase family AAA domain containing 1; Atg8a: Autophagy-related 8a; Atg9: Autophagy-related 9; Atg14: Autophagy-related 14; Atg18a: Autophagy-related 18a; ATP: adenosine triphosphate; bmm: brummer; CtsL1: Cathepsin L1; Idh: isocitrate dehydrogenase (NADP+); Cis1: CItrinin Sensitive knockout; GFP: green fluorescent protein; LDs: lipid droplets; LIRs:LC3-interacting regions; Lsd-1: Lipid storage droplet-1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Marf: Mitochondrial assembly regulatory factor; Miga: Mitoguardin; Msp1: Mitochondrial Sorting of Proteins 1; nmd: no mitochondrial derivative; PG: prothoracic gland; phtm: phantom; PNPLA2/ATGL: patatin like domain 2, triacylglycerol lipase; RFP: red fluorescent protein; RNAi: RNA interference; Syx17: Syntaxin 17; TA: tail-anchored; TEM: transmission electron microscopy; TOMM: translocase of outermitochondrial membrane; Tom20: Translocase of outer membrane 20; Tom40: Translocase of outer membrane 40.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144499826","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":"Sindbis virus is suppressed in the yellow fever mosquito <i>Aedes aegypti</i> by Atg6/BECN1 (autophagy-related 6)-mediated activation of autophagy.","authors":"Sujit Pujhari, Chan C Heu, Marco Brustolin, Rebecca M Johnson, Donghun Kim, Jason L Rasgon","doi":"10.1080/15548627.2025.2523735","DOIUrl":"10.1080/15548627.2025.2523735","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a critical modulator of pathogen invasion response in vertebrates and invertebrates. However, how it affects mosquito-borne viral pathogens that significantly burden public health remains relatively underexplored. To address this gap, we use a genetic approach to activate autophagy in the yellow fever mosquito (<i>Aedes aegypti</i>) infected with a recombinant Sindbis virus (SINV) expressing an autophagy activator. We first demonstrate a 17-amino acid peptide (\"AaBec-1\") derived from the <i>Ae. aegypti Atg6/BECN1</i> (Autophagy-related 6) gene is sufficient to induce autophagy in C6/36 mosquito cells, as marked by lipidation of Atg8 and puncta formation. Next, we engineered a recombinant SINV expressing the AaBec-1 peptide and used it to infect and induce autophagy in adult mosquitoes. We find that modulation of autophagy using this recombinant SINV negatively regulates production of infectious virus. The results from this study improve our understanding of the role of autophagy in regulating arbovirus infection in invertebrate hosts and highlight the potential for the autophagy pathway to be exploited for arbovirus control.<b>Abberviation</b>: C6/36- <i>Aedesalbopictus</i>cell line; dpi - days post-infection; FFA - focus-forming assay;MOI - multiplicity of infection; MTOR - Mechanistic target ofrapamycin kinase; PBS - phosphate-buffered saline; PCR - polymerase chain reaction; RT-PCR - reversetranscription-polymerase chain reaction; RNA - ribonucleic acid;SINV - Sindbis virus; Vero - African green monkey kidneyepithelial cells.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144509934","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":"Classical swine fever virus hijacks ESCRT-III and VPS4A to promote phagophore closure for accelerating mitophagy.","authors":"Yan Cheng, Yuhang Li, Xiaoqing Bi, Jinxia Chen, Bingqian Zhao, Jishan Bai, Yinbo Ye, Qi Dai, Linke Zou, Jing Chen, Xiuli Feng, Bin Zhou","doi":"10.1080/15548627.2025.2523734","DOIUrl":"10.1080/15548627.2025.2523734","url":null,"abstract":"<p><p>Classical swine fever virus (CSFV) infection induces complete mitophagy, which is essential for the clearance of damaged mitochondria. The endosomal sorting complex required for transport (ESCRT) machinery plays a vital role in mediating phagophore closure and autophagosome-lysosome fusion during starvation-induced autophagy. Nevertheless, its involvement in CSFV-induced mitophagy and the underlying mechanisms remain insufficiently understood. Here, we found that the ESCRT-III subunits including CHMP1A, CHMP1B, and CHMP4B, along with the AAA-ATPase VPS4, were actively recruited to autophagosomes during CSFV-induced mitophagy. Consistent with this, depletion of CHMP1A, CHMP1B, CHMP4B or VPS4A disrupted mitophagic flux, impairing both PINK1-PRKN-dependent and -independent pathways. Further investigations revealed that CSFV transiently recruited these subunits to nascent autophagosomes for phagophore sealing during mitophagy. Remarkably, multiple CSFV nonstructural proteins (NSPs) including NS3, NS4B, NS5A and NS5B interacted with these ESCRT key subunits and colocalized on mitophagosomes. Taken together, our study identifies CHMP1A, CHMP1B, CHMP4B, and VPS4A as pivotal regulators of phagophore closure in CSFV-induced mitophagy, unveiling novel mechanisms by which the virus manipulates host cellular pathways and highlighting potential therapeutic targets for infection control.Abbreviation: ATF4: activating transcription factor 4; ATG5: autophagy related 5; BafA1: bafilomycin A₁; BFP: blue fluorescent protein; BNIP3L/NIX: BCL2 interacting protein 3like; BSA: bovine serum albumin; CALCOCO2/NDP52: calcium binding andcoiled-coil domain 2; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CHMP: charged multivesicular body protein; COX4: cytochrome c oxidase subunit 4; CSFV: classical swine fever virus; DAPI: 4',6-diamidino-2-phenylindole; DN: dominant-negative; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; hpt: hours post-transfection; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; IB: immunoblotting; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFF: mitochondrial fission factor; MFN2: mitofusin 2; MITO: mitochondria; MOI: multiplicity of infection; mtDNA: mitochondrial DNA; OPTN: optineurin; PBS: phosphate-buffered saline; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RAPA: rapamycin; RFP: redfluorescent protein; RT-qPCR: reverse transcription-quantitativereal-time polymerase chain reaction; RT-PCR: real-time polymerasechain reaction; SD: standard deviation; siCtrl: negative control siRNA; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1: voltage dependent anion channel 1; VPS4A: vacuolar protein sorting 4 homolog A; WCL: whole-cell lysate; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144509953","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":"Statement of Retraction: GRSF1-mediated MIR-G-1 promotes malignant behavior and nuclear autophagy by directly upregulating TMED5 and LMNB1 in cervical cancer cells.","authors":"","doi":"10.1080/15548627.2025.2525726","DOIUrl":"https://doi.org/10.1080/15548627.2025.2525726","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585825","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":"Excessive autophagic degradation of MYLK3 causes sunitinib-induced cardiotoxicity.","authors":"Ziwei Pan, Lujie Zhu, Xiaochen Wang, Ning Huangfu, Pengpeng Su, Fangkun Yang, Xuyang Fu, Linbin Pu, Qiuli Fu, Jinghai Chen, Hanbin Cui, Ping Liang, Jiaxi Shen","doi":"10.1080/15548627.2025.2524290","DOIUrl":"10.1080/15548627.2025.2524290","url":null,"abstract":"<p><p>Sunitinib is a receptor tyrosine kinase inhibitor used for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Clinical data have shown that patients receiving sunitinib develop reduced cardiac function, arrhythmia and heart failure, thereby largely limiting its clinical use. However, the molecular mechanisms underlying sunitinib-induced arrhythmogenesis remain unclear. Here, utilizing the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model, we found that sunitinib caused a variety of deleterious phenotypes, including cardiomyocyte death, sarcomeric disorganization, irregular Ca²⁺ transients, impaired ATP2A2a/SERCA2a (ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 2a) activity, arrhythmia, and excessive macroautophagy/autophagy. Mechanistically, SQSTM1/p62 (sequestosome 1) interacts with MYLK3 (myosin light chain kinase 3) and drives excessive autophagic degradation of MYLK3 in sunitinib-treated iPSC-CMs. Downregulation of MYLK3 suppresses the phosphorylation of CAMK2/CAMKII (calcium/calmodulin dependent protein kinase II), thereby reducing the phosphorylation level of its downstream substrate PLN (phospholamban), leading to impaired ATP2A2a/SERCA2a activity and subsequent Ca²⁺ dyshomeostasis and arrhythmia. Moreover, pharmacological intervention of the cardiac myosin activator omecamtiv mecarbil (OM) or overexpression of MYLK3 significantly restored the expression of MYLK3 and reversed pathogenic phenotypes in sunitinib-treated iPSC-CMs. Nanoparticle delivery of OM effectively prevented sunitinib-induced cardiac dysfunction in mice. Our findings suggest that sunitinib-induced MYLK3 degradation causes the inhibition of the CAMK2-PLN-ATP2A2a signaling pathway and leads to sunitinib-induced arrhythmogenesis, and that MYLK3 can act as a novel cardioprotective target for sunitinib-induced cardiotoxicity.<b>Abbreviation</b>: ACTN:actinin alpha;APD:action potential duration; ATG:autophagy related;ATP2A2a/SERCA2a:ATPase sarcoplasmic/endoplasmicreticulum Ca2+ transporting 2a;BafA1:bafilomycin A₁;Caff: caffine; CAMK2/CAMKII:calcium/calmodulin dependent protein kinase II;CASP3:caspase 3;CQ, chloroquine;DADs:delayed afterdepolarizations; EAD:early afterdepolarization; ECG: electrocardiogram; EF: ejectionfraction; FS: fractional shortening; iPSC:inducedpluripotent stem cell;iPSC-CM: inducedpluripotent stem-cell-derived cardiomyocyte;ISO: isoprenaline; LVIDs: left ventricular end systolic diameter;LVIDd: left ventricular end diastolic diameter;MAP1LC3/LC3:microtubuleassociatedprotein 1 light chain 3;MYL2v/MLC2v:myosin light chain 2 v;MYLK3:myosin light chain kinase 3;OE: overexpression; OM:omecamtiv mecarbil; PLN: phospholamban;SIC:sunitinib-induced cardiotoxicity; SR:sarcoplasmic reticulum; TUNEL:TdT-mediated dUTP nick end labeling.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144499825","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":"Microaggrephagy: an ESCRT-I-PTPN23-dependent pathway for MAPT/tau aggregate clearance.","authors":"Shoshiro Hirayama, Shigeo Murata","doi":"10.1080/15548627.2025.2525866","DOIUrl":"10.1080/15548627.2025.2525866","url":null,"abstract":"<p><p>The clearance mechanisms for ubiquitinated protein aggregates, such as MAPT/tau in neurodegenerative diseases, remain incompletely understood, particularly regarding the role of microautophagy. To identify mediators of this process, we performed an unbiased genome-wide CRISPR knockout screen using cells propagating MAPT/tau repeat domain (MAPT/tauRD) aggregates. This screen identified the ESCRT-I complex and the accessory protein PTPN23 as essential for the clearance of ubiquitinated MAPT/tauRD aggregates via a microautophagy-dependent pathway, operating independently of macroautophagy and chaperone-mediated autophagy. We designate this pathway \"microaggrephagy\". Mechanistically, microaggrephagy involves the recognition of polyubiquitinated aggregates by the ESCRT-I subunit TSG101, with PTPN23 acting as an adaptor bridging ESCRT-I and ESCRT-III to facilitate microautophagic engulfment. Furthermore, a disease-associated mutation in the ESCRT-I component UBAP1 disrupts its interaction with PTPN23 and impairs MAPT/tau clearance, implicating dysfunction of this pathway in neurodegenerative pathogenesis. These findings establish microaggrephagy as a distinct cellular mechanism for degrading pathological protein aggregates, provide a molecular basis for its function, and suggest potential therapeutic targets for proteinopathies.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144509933","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":"Inhibition of lysosomal LAMTOR1 increases autophagy by suppressing the MTORC1 pathway to ameliorate lipid accumulations in MAFLD.","authors":"Yunyeong Jang, Minjeong Ko, Ju Yeon Lee, Jin Young Kim, Eun-Woo Lee, Ho Jeong Kwon","doi":"10.1080/15548627.2025.2519054","DOIUrl":"10.1080/15548627.2025.2519054","url":null,"abstract":"<p><p>Metabolic dysfunction-associated fatty liver disease (MAFLD) is a serious metabolic disorder characterized by fat accumulation in the liver, which can trigger liver inflammation and fibrosis, potentially leading to cirrhosis or liver cancer. Despite many studies, effective treatments for MAFLD remain elusive due to its complex etiology. In this study, we have focused on the discovery of therapeutic agents and molecular targets for MAFLD treatment. We demonstrated that the natural compound acacetin (ACA) alleviates MAFLD by regulating macroautophagy/autophagy in a CDAHFD mouse model of rapidly induced steatohepatitis. In addition, ACA inhibits lipid accumulation in 3T3-L1 adipocytes through autophagy induction. To identify the target responsible for the autophagy activity induced by ACA, we performed drug affinity responsive target stability (DARTS) combined with LC-MS/MS proteomic analysis. This led to the identification of LAMTOR1 (late endosomal/lysosomal adaptor, MAPK and MTOR activator 1), a lysosomal membrane adaptor protein. We found that binding of ACA to LAMTOR1 induces its release from the LAMTOR complex, leading to inhibition of MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1), thereby increasing autophagy. This process helps ameliorate metabolic disorders by modulating the MTORC1-AMPK axis. Genetic knockdown of LAMTOR1 phenocopies the effects of ACA treatment, further supporting the role of LAMTOR1 as a target of ACA. These findings suggest LAMTOR1 plays a crucial role in ACA's therapeutic effects on MAFLD. In summary, our study identifies LAMTOR1 as a key protein target of ACA, revealing a potential therapeutic avenue for MAFLD by modulating autophagy via the LAMTOR1-MTORC1-AMPK signaling pathway.<b>Abbreviations:</b> ACA: acacetin; ADGRE1/EMR1/F4/80: adhesion G protein-coupled receptor E1; AMPK: AMP-activated protein kinase; CDAHFD: choline-deficient amino acid-defined, high-fat diet; CETSA: cellular thermal shift assay; CQ: chloroquine; DARTS: drug affinity responsive target stability; DQ-BSA: dye quenched-bovine serum albumin; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; LAMP2: lysosomal associated membrane protein 2; LAMTOR1: late endosomal/lysosomal adaptor, MAPK and MTOR activator 1; LC-MS/MS: liquid chromatography-tandem mass spectrometry; MAFLD: metabolic dysfunction-associated fatty liver disease; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MASH: metabolic dysfunction-associated steatohepatitis; mRFP-GFP-MAP1LC3B: tandem fluorescent-tagged MAP1LC3B; MTORC1: mechanistic target of rapamycin complex 1; PA: palmitic acid; PRKAA: protein kinase AMP-activated catalytic subunit alpha; PLA: proximity ligation assay; Rapa: rapamycin; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; RRAG: Ras-related GTP-binding; SQSTM1: sequestosome 1; TFEB: transcription factor EB; VMP1: vacuole membrane protein 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478231","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 regulates cellular senescence by mediating the degradation of CDKN1A/p21 and CDKN2A/p16 through SQSTM1/p62-mediated selective autophagy in myxomatous mitral valve degeneration.","authors":"Qiyu Tang, Keyi Tang, Greg R Markby, Maciej Parys, Kanchan Phadwal, Vicky E MacRae, Brendan M Corcoran","doi":"10.1080/15548627.2025.2469315","DOIUrl":"10.1080/15548627.2025.2469315","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Myxomatous mitral valve degeneration (MMVD) is one of the most important age-dependent degenerative heart valve disorders in both humans and dogs. It is characterized by the aberrant remodeling of extracellular matrix (ECM), regulated by senescent myofibroblasts (aVICs) transitioning from quiescent valve interstitial cells (qVICs), primarily under TGFB1/TGF-β1 control. In the present study, we found senescent aVICs exhibited impaired macroautophagy/autophagy as evidenced by compromised autophagy flux and immature autophagosomes. MTOR-dependent autophagy induced by rapamycin and torin-1 attenuated cell senescence and decreased the expression of cyclin-dependent kinase inhibitors (CDKIs) CDKN2A/p16&lt;sup&gt;INK4A&lt;/sup&gt; and CDKN1A/p21&lt;sup&gt;CIP1&lt;/sup&gt;. Furthermore, induction of autophagy in aVICs by &lt;i&gt;ATG&lt;/i&gt; (autophagy related) gene overexpression restored autophagy flux, with a concomitant reduction in CDKN1A and CDKN2A expression and senescence-associated secretory phenotype (SASP). Conversely, autophagy deficiency induced CDKN1A and CDKN2A accumulation and SASP, whereas ATG re-expression alleviated senescent phenotypic transformation. Notably, CDKN1A and CDKN2A localized to autophagosomes and lysosomes following MTOR antagonism or MG132 treatment. SQSTM1/p62 was identified as the autophagy receptor to selectively sequester CDKN1A and CDKN2A cargoes for autophagic degradation. Our findings are the first demonstration that CDKN1A and CDKN2A are degraded through SQSTM1-mediated selective autophagy, independent of the ubiquitin-proteasome pathway. These data will inform development of therapeutic strategies for the treatment of canine and human MMVD, and for the treatment of Alzheimer disease, Parkinson disease and other age-related degenerative disorders.&lt;b&gt;Abbreviations&lt;/b&gt;: ACTA2/α-SMA: actin alpha 2, smooth muscle; AKT: AKT serine/threonine kinase; aVICs: activated valve interstitial cells; ATG: autophagy related; baf-A1: bafilomycin A&lt;sub&gt;1&lt;/sub&gt;; BrdU, bromodeoxyuridine; BSA: bovine serum albumin; CDKIs, cyclin-dependent kinase inhibitors; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; co-IP: co-immunoprecipitation; DMSO: dimethylsulfoxide; ECM, extracellular matrix; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; eGFP: green fluorescent protein; ELISA: enzyme-linked immunosorbent assay; HEK-293T, human embryonic kidney 293T; HRP: horseradish peroxidase; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: MAP1LC3/LC3-interacting region; MFS: Marfan syndrome; MKI67/Ki-67: marker of proliferation Ki-67; MMVD: myxomatous mitral valve degeneration; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; OE: overexpression; PBST, phosphate-buffered saline with 0.1% Tween-20; PCNA: proliferating cell nuclear antigen; PIK3CA/PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PLA: proximity ligation assays; PS","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1433-1455"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484986","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":"A distinctive form of autophagy induced by oncogenic RAS.","authors":"Xiaojuan Wang, Shulin Li, Min Zhang, Liang Ge","doi":"10.1080/15548627.2025.2468917","DOIUrl":"10.1080/15548627.2025.2468917","url":null,"abstract":"<p><p>RAS mutations enhance macroautophagy/autophagy in tumor cells, crucial for their growth and survival, making autophagy a promising therapeutic target for RAS-mutant cancers. However, the distinction between RAS-induced autophagy and physiological autophagy is not well understood. We recently identified a unique form of autophagy, RAS-induced non-canonical autophagy via ATG8ylation (RINCAA), which differs from starvation-induced autophagy. RINCAA is regulated by different sets of autophagic factors and forms structures distinct from the double-membrane autophagosome known as RAS-induced multivesicular/multilaminar bodies of ATG8ylation (RIMMBA). A key feature of RINCAA is the phosphorylation of PI4KB by ULK1, and inhibiting this phosphorylation shows superior effects compared to general autophagy inhibitors. This work suggests a potential for specifically targeting autophagy in RAS-driven cancers as a therapeutic strategy.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1608-1610"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485029","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 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":"1614-1615"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626860","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}