Autophagy最新文献

{"title":"Visualization of autophagic structures near solid polyQ aggregates reveals how they undermine autophagy.","authors":"Hana Popelka, Daniel J Klionsky","doi":"10.1080/15548627.2025.2503578","DOIUrl":"https://doi.org/10.1080/15548627.2025.2503578","url":null,"abstract":"<p><p>Aggregates of polyglutamine (polyQ) repeat extensions are known markers of several, predominantly inherited, neurodegenerative diseases. Removal of polyQ is essential for cellular proteostasis and macroautophagy/autophagy has been proposed to be an important tool in the clearance of polyQ aggregates. The mechanism of recognition and encapsulation of these aggregates within autophagosomes is largely unknown. A study described in this article employed <i>in situ</i> correlative cryo-electron tomography to visualize polyQ aggregates interacting with autophagic compartments. The tomograms revealed that only amorphous polyQ, but not fibrils, are engulfed by double-membrane structures and that SQSTM1/p62 is the receptor involved in recognition of polyQ during autophagy. Solidified amorphous polyQ and subsequent fibrils arrest the normal formation of autophagosomes and impair autophagy. Findings of the study described here have implications for therapies that rely on autophagy in targeting polyQ neurodegeneration.<b>Abbreviation:</b> cryo-CLEM, cryo-correlative light and electron microscopy; cryo-ET, cryo-electron tomography; ER, endoplasmic reticulum; HD, Huntington disease; HTT, huntingtin; polyQ, polyglutamine repeats.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082732","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":"Biochemical investigation of LC3/GABARAP-ligand interaction as an important quality measure for LC3/GABARAP-targeting small molecules: addendum to the guidelines (4th edition).","authors":"Martin P Schwalm, Christopher Lenz, Krishna Saxena, Daniel J Klionsky, Ewgenij Proschak, Stefan Knapp","doi":"10.1080/15548627.2025.2498506","DOIUrl":"https://doi.org/10.1080/15548627.2025.2498506","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) represents a new therapeutic modality that allows the targeting of proteins that are considered undruggable by conventional small molecules. While TPD approaches via the ubiquitin-proteasome system are well established and validated, additional degradation pathways still require rigorous characterization. Here, we focus on macroautophagy/autophagy tethering compounds, a class of small molecules, designed to recruit cargo to LC3/GABARAP proteins for subsequent autophagosome-dependent degradation. We provide guidance for the biophysical and structural characterization of small molecule modulators for studying LC3/GABARAP-ligand interactions. In addition, we discuss potential limitations of autophagy-based TPD systems and emphasize the need for rigorous quality control in the development of LC3/GABARAP-targeting small molecules.<b>Abbreviations</b>: DSF: differential scanning fluorimetry; FP: fluorescence polarization; FRET: Förster/fluorescence resonance energy transfer; HTRF: homogeneous time-resolved fluorescence; ITC: isothermal titration calorimetry; LIR: LC3-interacting region; MGs: molecular glues; NMR: nuclear magnetic resonance; PROTACs: PROteolysis-TArgeting Chimeras; SPR: surface plasmon resonance; TPD: targeted protein degradation; TR-FRET: time-resolved Förster/fluorescence resonance energy transfer; UPS: ubiquitin-proteasome system.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-5"},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065364","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":"MoSec13 combined with MoGcn5b modulates MoAtg8 acetylation and regulates autophagy in <i>Magnaporthe oryzae</i>.","authors":"Hui Qian, Ming-Hua Wu, Wen-Hui Zhao, Xue-Ming Zhu, Li-Xiao Sun, Jian-Ping Lu, Daniel J Klionsky, Fu-Cheng Lin, Xiao-Hong Liu","doi":"10.1080/15548627.2025.2499289","DOIUrl":"https://doi.org/10.1080/15548627.2025.2499289","url":null,"abstract":"<p><p>Macroautophagy/autophagy is an evolutionarily conserved cellular degradation process that is crucial for cellular homeostasis in <i>Magnaporthe oryzae</i>. However, the precise regulatory mechanisms governing autophagy in this organism remain unclear. In this study, we found a multiregional localization of MoSec13 to the vesicle membrane, endoplasmic reticulum, nucleus, and perinucleus. MoSec13 negatively regulated autophagy through specific amino acid residues in its own WD40 structural domain by interacting with MoAtg7 and MoAtg8. We also found that the histone acetyltransferase MoGcn5b mediated the acetylation of MoAtg8 and regulated autophagy activity. Subsequently, we further determined that MoSec13 regulated the acetylation status of MoAtg8 by controlling the interaction between MoGcn5b and MoAtg8 in the nucleus. In addition, MoSec13 maintained lipid homeostasis by controlling TORC2 activity. This multilayered integration establishes MoSec13 as an essential node within the autophagic regulatory network. Our findings fill a critical gap in understanding the role of Sec13 in autophagy of filamentous fungi and provide a molecular foundation for developing new therapeutic strategies against rice blast fungus.<b>ABBREVIATIONS</b> BFA: brefeldin A; BiFC: bimolecular fluorescence complementation; CM: complete medium; CMAC: 7-amino-4-chloromethylcoumarin; Co-IP: co-immunoprecipitation; COPII: coat complex II; GFP: green fluorescent protein; HPH: hygromycin phosphotransferase; MM-N: nitrogen-starvation conditions; NPC: nuclear pore complex; PAS: phagophore assembly site; PE: phosphatidylethanolamine; UPR: unfolded protein response.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055275","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":"METTL3-dependent m⁶A modification of SNAP29 induces \"autophagy-mitochondrial crisis\" in the ischemic microenvironment after soft tissue transplantation.","authors":"Ningning Yang, Yingying Lai, Gaoxiang Yu, Xuzi Zhang, Jingwei Shi, Linyi Xiang, Jiacheng Zhang, Yuzhe Wu, Xiaoqiong Jiang, Xuanlong Zhang, Liangliang Yang, Weiyang Gao, Jian Ding, Xiangyang Wang, Jian Xiao, Kailiang Zhou","doi":"10.1080/15548627.2025.2493455","DOIUrl":"https://doi.org/10.1080/15548627.2025.2493455","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Necrosis at the ischemic distal end of flap transplants increases patients' pain and economic burden. Reactive oxygen species (ROS) and mitochondrial damage are crucial in regulating parthanatos, but the mechanisms linking disrupted macroautophagic/autophagic flux to parthanatos in ischemic flaps remain unclear. The results of western blotting, immunofluorescence staining, and a proteomic analysis revealed that the autophagic protein SNAP29 was deficient in ischemic flaps, resulting in disrupted autophagic flux, increased ROS-induced parthanatos, and aggravated ischemic flap necrosis. The use of AAV vector to restore SNAP29 &lt;i&gt;in vivo&lt;/i&gt; mitigated the disruption of autophagic flux and parthanatos. Additionally, quantification of the total m&lt;sup&gt;6&lt;/sup&gt;A level and RIP-qPCR, MeRIP-qPCR, and RNA stability assessments were performed to determine differential &lt;i&gt;Snap29&lt;/i&gt; mRNA m&lt;sup&gt;6&lt;/sup&gt;A methylation levels and mRNA stability in ischemic flaps. Various &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt; tests were conducted to verify the ability of METTL3-mediated m&lt;sup&gt;6&lt;/sup&gt;A methylation to promote SNAP29 depletion and disrupt autophagic flux. Finally, we concluded that restoring SNAP29 by inhibiting METTL3 and YTHDF2 reversed the \"autophagy-mitochondrial crisis\", defined for the first time as disrupted autophagic flux, mitochondrial damage, mitochondrial protein leakage, and the occurrence of parthanatos. The reversal of this crisis ultimately promoted the survival of ischemic flaps.&lt;b&gt;Abbreviations&lt;/b&gt;: AAV = adeno-associated virus; ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta; AIFM/AIF = apoptosis-inducing factor, mitochondrion-associated; ALKBH5 = alkB homolog, RNA demythelase; Baf A1 = bafilomycin A&lt;sub&gt;1&lt;/sub&gt;; CQ = chloroquine; DHE = dihydroethidium; ECs = endothelial cells; F-CHP = 5-FAM-conjugated collagen-hybridizing peptide; GO = gene ontology; HUVECs = human umbilical vein endothelial cells; KEGG = Kyoto Encyclopedia of Genes and Genomes; LC-MS/MS = liquid chromatography-tandem mass spectrometry; LDBF = laser doppler blood flow; m&lt;sup&gt;6&lt;/sup&gt;A = N6-methyladenosine; MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3; MeRIP = methylated RNA immunoprecipitation; METTL3 = methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit; NAC = N-acetylcysteine; OGD = oxygen glucose deprivation; PAR = poly (ADP-ribose); PARP1 = poly (ADP-ribose) polymerase family, member 1; PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1; ROS = reactive oxygen species; RT-qPCR = reverse transcription quantitative polymerase chain reaction; RIP = RNA immunoprecipitation; SNAP29 = synaptosomal-associated protein 29; SNARE = soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1 = sequestosome 1; SRAMP = sequence-based RNA adenosine methylation site predicting; STX17 = syntaxin 17; TMT = tandem mass tag; TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling; VAMP8 = vesicle-associated membra","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-24"},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055272","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":"SNX10 at the crossroad of endocytosis and piecemeal mitophagy.","authors":"Laura Trachsel-Moncho, Benan John Mathai, Chiara Veroni, Anne Simonsen","doi":"10.1080/15548627.2025.2499641","DOIUrl":"https://doi.org/10.1080/15548627.2025.2499641","url":null,"abstract":"<p><p>Mitophagy targets damaged or dysfunctional mitochondria for lysosomal degradation. While canonical mitophagy pathways target the whole mitochondria for lysosomal degradation, it has become clear that selected mitochondrial components can be targeted for lysosomal degradation via other pathways, such as piecemeal mitophagy or mitochondria-derived vesicles. In a recent study, we identified the PX domain-containing endosomal protein SNX10 as a negative modulator of piecemeal mitophagy. Endosomal SNX10-positive vesicles dynamically interact with mitochondria and acquire selected mitochondrial proteins upon hypoxia. Zebrafish larvae lacking Snx10 show elevated Cox-IV degradation, increased levels of reactive oxygen species (ROS), and ROS-dependent neuronal death.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055061","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":"ATP2A2 regulates STING1/MITA-driven signal transduction including selective autophagy.","authors":"Xue Yang, Linyue Lv, Yuelan Zhang, Zhuyou Zhang, Shaowei Zeng, Xinyi Zhang, Qinyang Wang, Martin Dorf, Shitao Li, Bishi Fu","doi":"10.1080/15548627.2025.2496786","DOIUrl":"https://doi.org/10.1080/15548627.2025.2496786","url":null,"abstract":"<p><p>STING1/MITA not only induces innate immune responses but also triggers macroautophagy/autophagy to selectively degrade signaling molecules. However, the molecular mechanisms regulating STING1-mediated selective autophagy remain unclear. Here, we first report that ATP2A2 directly interacts with STING1, regulating STING1-mediated innate immune response by modulating its polymerization and trafficking, thereby inhibiting DNA virus infection. Notably, while screening for reticulophagy receptors involved in STING1-mediated selective autophagy, we identified SEC62 as an important receptor protein in STING1-mediated reticulophagy. Mechanistically, SEC62 strengthens its interaction with STING1 upon activation and concurrently facilitates STING1-mediated reticulophagy upon starvation, which are dependent on ATP2A2. Furthermore, knocking down SEC62 in WT cells inhibits STING1-mediated MAP1LC3B/LC3B lipidation and autophagosome formation, an effect that is lost in <i>ATP2A2</i> knockout cells, suggesting that SEC62's role in STING1-mediated selective autophagy is ATP2A2 dependent. Thus, our findings identify the reticulophagy receptor SEC62 as a novel receptor protein regulating STING1-mediated selective autophagy, providing new insight into the mechanism regarding a reticulophagy receptor in the process of STING1-induced selective autophagy.<b>Abbrevations:</b> aa: amino acids; AP-MS: affinity tag purification-mass spectrometry; ATP2A1: ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 1; ATP2A2: ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 2; ATP2A3: ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 3; CANX: calnexin; CCPG1: cell cycle progression 1; CGAS: cyclic GMP-AMP synthase; ctDNA: calf thymus DNA; dsRNA: double-stranded RNA; diABZI: diamidobenzimidazole; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment; EBSS: Earle's Balanced Salt Solution; EV: empty vector; FL: full length; GOLGA2/GM130: golgin A2; HSV-1: herpes simplex virus type 1; IRF3: interferon regulatory factor 3; IFNs: type I interferons; ISD: interferon stimulatory DNA; KO: knockout; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; poly(I:C): polyinosinic-polycytidylic acid; NBR1: NBR1 autophagy cargo receptor; PRR: pattern recognition receptor; reticulophagy: selective autophagic degradation of the ER; RETREG1/FAM134B: reticulophagy regulator 1; RIGI: RNA sensor RIG-I; RTN3L: reticulon 3; SEC62: SEC62 homolog, preprotein translocation factor; SeV: Sendai virus; STIM1: stromal interaction molecule 1; STING1/MITA: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TEX264: testis expressed 264, ER-phagy receptor; TMX1: thioredoxin related transmembrane protein 1; VSV: vesicular stomatitis virus; VACV: vaccinia virus; ZMPSTE24: zinc metallopeptidase STE24.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-16"},"PeriodicalIF":0.0,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053588","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":"PINK1-dependent NFKB signaling contributes to amyloid pathology in Alzheimer disease.","authors":"Fang Du, Qing Yu, Gang Hu, Chyuan-Sheng Lin, Shirley ShiDu Yan","doi":"10.1080/15548627.2025.2463322","DOIUrl":"https://doi.org/10.1080/15548627.2025.2463322","url":null,"abstract":"<p><p>Mitochondrial dysfunction plays a preponderant role in the development of Alzheimer disease (AD). We have demonstrated that activation of PINK1 (PTEN induced kinase 1)-dependent mitophagy ameliorates amyloid pathology, attenuates mitochondrial and synaptic dysfunction, and improves cognitive function. However, the underlying mechanisms remain largely unknown. Using a newly generated PINK1-AD transgenic mouse model and AD neuronal cell lines, we provide substantial evidence supporting the contribution of PINK1-mediated mitochondrial ROS (reactive oxygen species) and NFKB/NF-κB (nuclear factor kappa B) signaling to altering APP (amyloid beta precursor protein) processing and Aβ metabolism. Enhancing neuronal PINK1 is sufficient to suppress Aβ-induced activation of NFKB signal transduction in PINK1-overexpressed Aβ-AD mice and Aβ-producing neurons. Blocking PINK1-mediated NFKB activation inhibits activities of BACE1 (beta-secretase 1) and γ-secretase, which are key enzymes for cleavage of APP processing to produce Aβ. Conversely, loss or knockdown of PINK1 produces excessive ROS, along with increased phosphorylated NFKB1/p50 and RELA/p65 subunits, APP-related BACE1 and γ-secretase, and Aβ accumulation. Importantly, these detrimental effects were robustly blocked by the addition of scavenging PINK1 Aβ-induced mitochondrial ROS, leading to the suppression of NFKB activation, restoration of normal APP processing, and limitation of Aβ accumulation. Thus, our findings highlight a novel mechanism underlying PINK1-mediated modulation of Aβ metabolism <i>via</i> a ROS-NFKB-APP processing nexus. Activation of PINK1 signaling could be a potential therapeutic avenue for the early stages of AD by combining improving mitochondrial quality control with limiting amyloid pathology in AD.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009746","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":"AlphaFold2 SLiM screen for LC3-LIR interactions in autophagy.","authors":"Jan Felix Maximilian Stuke, Gerhard Hummer","doi":"10.1080/15548627.2025.2493999","DOIUrl":"https://doi.org/10.1080/15548627.2025.2493999","url":null,"abstract":"&lt;p&gt;&lt;p&gt;In selective macroautophagy/autophagy, cargo recruitment is mediated by MAP1LC3/LC3-interacting regions (LIRs)/Atg8-family interacting motifs (AIMs) in the cargo or cargo receptor proteins. The binding of these motifs to LC3/Atg8 proteins at the phagophore membrane is often modulated by post-translational modifications, especially phosphorylation. As a challenge for computational LIR predictions, sequences may contain the short canonical (W/F/Y)XX(L/I/V) motif without being functional. Conversely, LIRs may be formed by non-canonical but functional sequence motifs. AlphaFold2 has proven to be useful for LIR predictions, even if some LIRs are missed and proteins with thousands of residues reach the limits of computational feasibility. We present a fragment-based approach to address these limitations. We find that fragment length and phosphomimetic mutations modulate the interactions predicted by AlphaFold2. Systematic fragment screening for a range of target proteins yields structural models for interactions that AlphaFold2 and AlphaFold3 fail to predict for full-length targets. We provide guidance on fragment choice, sequence tuning, LC3 isoform effects, and scoring for optimal LIR screens. Finally, we also test the transferability of this general framework to SUMO-SIM interactions, another type of protein-protein interaction involving short linear motifs (SLiMs).&lt;b&gt;Abbreviations&lt;/b&gt;: 2-HP-LIR: ncLIR binding either or both HPs with non-canonical residues; AIM: Atg8-family interacting motif; ap. LIR: antiparallel LIR; &lt;i&gt;A.t&lt;/i&gt;.; &lt;i&gt;Arabidopsis thaliana&lt;/i&gt;; AT5G06830/C53 (&lt;i&gt;A.t&lt;/i&gt;.): CDK5RAP3-like protein; Atg8/ATG8: autophagy related 8, in yeast and plants, respectively; ATG8CL: ATG8C-like of &lt;i&gt;Solanum tuberosum&lt;/i&gt; (potato); ATG8E: ATG8e of &lt;i&gt;A.t&lt;/i&gt;.; Av. num. of contacts: average number of heavy atom contacts; BCL2: BCL2 apoptosis regulator; BNIP3: BCL2 interacting protein 3; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CALR: calreticulin; can. LIR: canonical LIR; CDF: cumulative distribution function; CDK5RAP3/C53 (&lt;i&gt;H.s&lt;/i&gt;.): CDK5 regulatory subunit associated protein 3; [DE]W[DE]-LIR: TRIM5-like ncLIR; DSK2A: ubiquitin domain-containing protein DSK2a; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; HP0/1/2: hydrophobic pocket 0/1/2; HP0-LIR: ncLIR engaging HP0; &lt;i&gt;H.s&lt;/i&gt;.; &lt;i&gt;Homo sapiens&lt;/i&gt;; lcLIR: low-confidence LIR (ncLIR not similar to previously characterized ncLIRs); LDS: LIR-docking site; LIR: LC3-interacting region; LO score: length-weighted fraction of occurrence score; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MD: molecular dynamics; MEFV/pyrin: MEFV innate immunity regulator, pyrin; minPAE: minimum PAE; MSA: multiple sequence alignment; ncLIR: non-canonical LIR; NPC: nuclear pore complex; Nup159: nucleoporin 159; NUP214: nucleoporin 214; OPTN: optineurin; other@LDS: other interact","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060841","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":"Blocking autophagosome closure manifests the roles of mammalian Atg8-family proteins in phagophore formation and expansion during nutrient starvation.","authors":"Van Bui, Xinwen Liang, Yansheng Ye, William Giang, Fang Tian, Yoshinori Takahashi, Hong-Gang Wang","doi":"10.1080/15548627.2024.2443300","DOIUrl":"10.1080/15548627.2024.2443300","url":null,"abstract":"<p><p>Macroautophagy/autophagy, an evolutionarily conserved cellular degradation pathway, involves phagophores that sequester cytoplasmic constituents and mature into autophagosomes for subsequent lysosomal delivery. The <i>ATG8</i> gene family, comprising the <i>MAP1LC3/LC3</i> and <i>GABARAP/GBR</i> subfamilies in mammals, encodes ubiquitin-like proteins that are conjugated to phagophore membranes during autophagosome biogenesis. A central question in the field is how Atg8-family proteins are precisely involved in autophagosome formation, which remains controversial and challenging, at least in part due to the short lifespan of phagophores. In this study, we depleted the autophagosome closure regulator VPS37A to arrest autophagy at the vesicle completion step and determined the roles of mammalian Atg8-family proteins (mATG8s) in nutrient starvation-induced autophagosome biogenesis. Our investigation revealed that <i>LC3</i> loss hinders phagophore formation, while <i>GBR</i> loss impedes both phagophore formation and expansion. The defect in membrane expansion by <i>GBR</i> loss appears to be attributed to compromised recruitment of ATG proteins containing an LC3-interacting region (LIR), including ULK1 and ATG3. Moreover, a combined deficiency of both <i>LC3</i> and <i>GBR</i> subfamilies nearly completely inhibits phagophore formation, highlighting their redundant regulation of this process. Consequently, cells lacking all <i>mATG8</i> members exhibit defects in downstream events such as ESCRT recruitment and autophagic flux. Collectively, these findings underscore the critical roles of mammalian Atg8-family proteins in phagophore formation and expansion during autophagy.<b>Abbreviation</b>: AIM: Atg8-family interacting motif; ADS: Atg8-interacting motif docking site; ATG: autophagy related; BafA1: bafilomycin A₁; CL: control; ESCRT: endosomal sorting complex required for transport; FACS: fluorescence activated cell sorting; GBR: GABARAP; GBRL1: GABARAPL1; GBRL2: GABARAPL2; GBRL3: GABARAPL3; HKO: hexa-knockout; IP: immunoprecipitation; KO: knockout; LDS: LC3-interacting-region docking site; LIR: LC3-interacting region; mATG8: mammalian Atg8-family protein; MIL: membrane-impermeable ligands; MPL: membrane-permeable ligands; RT: room temperature; Stv: starved; TKO: triple-knockout; TMR: tetramethylrhodamine; UEVL: ubiquitin E2 variant-like; WCLs: whole cell lysates; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1059-1074"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855871","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":"Quality control of ABCD3 by the VCP-FAF2 complex suppresses excessive pexophagy.","authors":"Fumika Koyano, Noriyuki Matsuda","doi":"10.1080/15548627.2025.2461473","DOIUrl":"10.1080/15548627.2025.2461473","url":null,"abstract":"<p><p>Peroxisomes play many crucial roles in cells such as the oxidation of very long-chain fatty acids and the detoxification of hydrogen peroxide. Given that peroxisomes are constantly exposed to various stresses, it is reasonable to assume that peroxisomes undergo robust quality- and quantity-control. Although the molecular mechanisms of this control remain to be fully elucidated, we recently demonstrated that the VCP-FAF2 complex plays a pivotal role in peroxisomal maintenance. More specifically, we found that the complex prevents excessive selective autophagic peroxisomal degradation (pexophagy) by regulating the accumulation of the ubiquitinated form of peroxisomal membrane protein ABCD3.<b>Abbreviation:</b> ABCD3: ATP binding cassette subfamily D member 3, CALCOCO2: calcium binding and coiled-coil domain 2, FAF2: Fas associated factor family member 2, OPTN: optineurin, RB1CC1: RB1 inducible coiled-coil 1, SQSTM1: sequestosome 1, TAX1BP1: Tax1 binding protein 1, UBA domain: ubiquitin-associated domain, VCP: valosin containing protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1169-1170"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392722","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}