Autophagy最新文献

{"title":"Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner.","authors":"Jin Ju Lim, Sujin Noh, Woojun Kang, Bom Hyun, Byung-Hoon Lee, Seogang Hyun","doi":"10.1080/15548627.2024.2389607","DOIUrl":"10.1080/15548627.2024.2389607","url":null,"abstract":"<p><p>Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in <i>Drosophila</i> and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging <i>Drosophila</i> flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by <i>foxo</i> mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.<b>Abbreviations</b>: AAAs: amino acid analogs; foxo: forkhead box, sub-group O; IFMs: indirect flight muscles; UPS: ubiquitin-proteasome system; USP14: ubiquitin specific peptidase 14.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903915","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":"ZDHHC7-mediated <i>S</i>-palmitoylation of ATG16L1 facilitates LC3 lipidation and autophagosome formation.","authors":"Fujing Wei, Yu Wang, Jia Yao, Ligang Mei, Xue Huang, Hesheng Kong, Jing Chen, Xiaorong Chen, Lu Liu, Zhuolin Wang, Jiaxin Wang, Jiong Song, Eryan Kong, Aimin Yang","doi":"10.1080/15548627.2024.2386915","DOIUrl":"10.1080/15548627.2024.2386915","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a fundamental cellular catabolic process that delivers cytoplasmic components into double-membrane vesicles called autophagosomes, which then fuse with lysosomes and their contents are degraded. Autophagy recycles cytoplasmic components, including misfolded proteins, dysfunctional organelles and even microbial invaders, thereby playing an essential role in development, immunity and cell death. Autophagosome formation is the main step in autophagy, which is governed by a set of ATG (autophagy related) proteins. ATG16L1 interacts with ATG12-ATG5 conjugate to form an ATG12-ATG5-ATG16L1 complex. The complex acts as a ubiquitin-like E3 ligase that catalyzes the lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3), which is crucial for autophagosome formation. In the present study, we found that ATG16L1 was subject to <i>S</i>-palmitoylation on cysteine 153, which was catalyzed by ZDHHC7 (zinc finger DHHC-type palmitoyltransferase 7). We observed that re-expressing ATG16L1 but not the <i>S</i>-palmitoylation-deficient mutant ATG16L1^C153S rescued a defect in the lipidation of LC3 and the formation of autophagosomes in <i>ATG16L1</i>-KO (knockout) HeLa cells. Furthermore, increasing ATG16L1 <i>S</i>-palmitoylation by ZDHHC7 expression promoted the production of LC3-II, whereas reducing ATG16L1 <i>S</i>-palmitoylation by <i>ZDHHC7</i> deletion inhibited the LC3 lipidation process and autophagosome formation. Mechanistically, the addition of a hydrophobic 16-carbon palmitoyl group on Cys153 residue of ATG16L1 enhances the formation of ATG16L1-WIPI2B complex and ATG16L1-RAB33B complex on phagophore, thereby facilitating the LC3 lipidation process and autophagosome formation. In conclusion, <i>S</i>-palmitoylation of ATG16L1 is essential for the lipidation process of LC3 and the formation of autophagosomes. Our research uncovers a new regulatory mechanism of ATG16L1 function in autophagy.<b>Abbreviation</b>: ABE: acyl-biotin exchange; ATG: autophagy related; Baf-A1: bafilomycin A₁; 2-BP: 2-bromopalmitate; CCD: coiled-coil domain; co-IP: co-immunoprecipitation; CQ: chloroquine; EBSS: Earle's balanced salt solution; HAM: hydroxylamine; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NP-40: Nonidet P-40; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; PtdIns3K-C1: class III phosphatidylinositol 3-kinase complex I; PTM: post-translational modification; RAB33B: RAB33B, member RAS oncogene family; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SDS: sodium dodecyl sulfate; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscope; WD: tryptophan and aspartic acid; WIPI2B: WD repeat domain, phosphoinositide interacting 2B; WT: wild-type; ZDHHC: zinc finger DHHC-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861915","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":"Ca²⁺ as an essential signaling molecule controlling Snf1-mediated Atg1 activation.","authors":"Yanyang Wu, Cong Yi","doi":"10.1080/15548627.2024.2389483","DOIUrl":"10.1080/15548627.2024.2389483","url":null,"abstract":"<p><p>Macroautophagy/autophagy is essential for maintaining glucose homeostasis, but the mechanisms by which cells sense glucose starvation and initiate autophagy are not yet fully understood. Recently, we reported that the assembly of a Ca²⁺-triggered Snf1-Bmh1/Bmh2-Atg11 complex initiates autophagy in response to glucose starvation. Our research reveals that during glucose starvation, the efflux of vacuolar Ca²⁺ increases cytoplasmic Ca²⁺ levels, which activates the protein kinase Rck2. Rck2-mediated phosphorylation of Atg11 enhances its interaction with Bmh1 and Bmh2. This interaction recruits the Snf1-Sip1-Snf4 complex, which is located on the vacuolar membrane, to the phagophore assembly site (PAS), leading to the activation of Atg1 and the initiation of autophagy. In summary, we have identified a previously unrecognized signaling pathway involved in glucose starvation-induced autophagy, where Ca²⁺ acts as a fundamental signaling molecule that links energy stress to the formation of the autophagy initiation complex.<b>Abbreviation</b>: AMPK: AMP-activated protein kinase; <i>ATG</i>: autophagy related; co-IP: co-immunoprecipitation; MAPK: mitogen-activated protein kinase; PAS: phagophore assembly site; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895084","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":"PRRSV utilizes MALT1-regulated autophagy flux to switch virus spread and reserve.","authors":"Han Gu, He Qiu, Haotian Yang, Zhuofan Deng, Shengkun Zhang, Liuyang Du, Fang He","doi":"10.1080/15548627.2024.2386195","DOIUrl":"10.1080/15548627.2024.2386195","url":null,"abstract":"<p><p>Porcine reproductive and respiratory syndrome virus (PRRSV) is a major swine pathogen, which can survive host antiviral immunity with various mechanisms. PRRSV infection induces macroautophagy/autophagy, facilitating virus replication. MALT1, a central immune regulator, was manipulated by PRRSV to optimize viral infection at different stages of the virus cycle. In this study, the key role of MALT1 in autophagy regulation during PRRSV infection was characterized, enlightening the role of autophagy flux in favor of virus spread and persistent infection. PRRSV-induced autophagy was confirmed to facilitate virus proliferation. Furthermore, autophagic fusion was dynamically regulated during PRRSV infection. Importantly, PRRSV-induced MALT1 facilitated autophagosome-lysosome fusion and autolysosome formation, thus contributing to autophagy flux and virus proliferation. Mechanically, MALT1 regulated autophagy via mediating MTOR-ULK1 and -TFEB signaling and affecting lysosomal homeostasis. MALT1 inhibition by inhibitor Mi-2 or RNAi induced lysosomal membrane permeabilization (LMP), leading to the block of autophagic fusion. Further, MALT1 overexpression alleviated PRRSV-induced LMP via inhibiting ROS generation. In addition, blocking autophagy flux suppressed virus release significantly, indicating that MALT1-maintained complete autophagy flux during PRRSV infection favors successful virus spread and its proliferation. In contrast, autophagosome accumulation upon MALT1 inhibition promoted PRRSV reserve for future virus proliferation once the autophagy flux recovers. Taken together, for the first time, these findings elucidate that MALT1 was utilized by PRRSV to regulate host autophagy flux, to determine the fate of virus for either proliferation or reserve.<b>Abbreviations</b>: 3-MA: 3-methyladenine; BafA1: bafilomycin A₁; BFP/mBFP: monomeric blue fluorescent protein; CQ: chloroquine; DMSO: dimethyl sulfoxide; dsRNA: double-stranded RNA; GFP: green fluorescent protein; hpi: hours post infection; IFA: indirect immunofluorescence assay; LAMP1: lysosomal associated membrane protein 1; LGALS3: galectin 3; LLOMe: L-leucyl-L-leucine-methyl ester; LMP: lysosomal membrane permeabilization; mAb: monoclonal antibody; MALT1: MALT1 paracaspase; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NFKB/NF-κB: nuclear factor kappa B; nsp: nonstructural protein; ORF: open reading frame; pAb: polyclonal antibody; PRRSV: porcine reproductive and respiratory syndrome virus; PRRSV-N: PRRSV nucleocapsid protein; Rapa: rapamycin; RFP: red fluorescent protein; ROS: reactive oxygen species; SBI: SBI-0206965; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TCID₅₀: 50% tissue culture infective dose; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857388","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":"Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy.","authors":"Jiajia Wang, Yueping Qiu, Lijun Yang, Jincheng Wang, Jie He, Chengwu Tang, Zhaoxu Yang, Wenxiang Hong, Bo Yang, Qiaojun He, Qinjie Weng","doi":"10.1080/15548627.2024.2384348","DOIUrl":"https://doi.org/10.1080/15548627.2024.2384348","url":null,"abstract":"<p><p>Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.<b>Abbreviation:</b> AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic - pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891251","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":"Emerging roles of ATG9/ATG9A in autophagy: implications for cell and neurobiology.","authors":"Jiyoung Choi, Haeun Jang, Zhao Xuan, Daehun Park","doi":"10.1080/15548627.2024.2384349","DOIUrl":"https://doi.org/10.1080/15548627.2024.2384349","url":null,"abstract":"<p><p>Atg9, the only transmembrane protein among many autophagy-related proteins, was first identified in the year 2000 in yeast. Two homologs of Atg9, ATG9A and ATG9B, have been found in mammals. While ATG9B shows a tissue-specific expression pattern, such as in the placenta and pituitary gland, ATG9A is ubiquitously expressed. Additionally, ATG9A deficiency leads to severe defects not only at the molecular and cellular levels but also at the organismal level, suggesting key and fundamental roles for ATG9A. The subcellular localization of ATG9A on small vesicles and its functional relevance to autophagy have suggested a potential role for ATG9A in the lipid supply during autophagosome biogenesis. Nevertheless, the precise role of ATG9A in the autophagic process has remained a long-standing mystery, especially in neurons. Recent findings, however, including structural, proteomic, and biochemical analyses, have provided new insights into its function in the expansion of the phagophore membrane. In this review, we aim to understand various aspects of ATG9 (in invertebrates and plants)/ATG9A (in mammals), including its localization, trafficking, and other functions, in nonneuronal cells and neurons by comparing recent discoveries related to ATG9/ATG9A and proposing directions for future research.<b>Abbreviation</b>: AP-4: adaptor protein complex 4; ATG: autophagy related; cKO: conditional knockout; CLA-1: CLArinet (functional homolog of cytomatrix at the active zone proteins piccolo and fife); cryo-EM: cryogenic electron microscopy; ER: endoplasmic reticulum; KO: knockout; PAS: phagophore assembly site; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SV: synaptic vesicle; TGN: trans-Golgi network; ULK: unc-51 like autophagy activating kinase; WIPI2: WD repeat domain, phosphoinositide interacting 2.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891250","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":"Emerging dimensions of autophagy in melanoma.","authors":"Christian Pangilinan, Daniel J Klionsky, Chengyu Liang","doi":"10.1080/15548627.2024.2330261","DOIUrl":"10.1080/15548627.2024.2330261","url":null,"abstract":"<p><p>Macroautophagy/autophagy has previously been regarded as simply a way for cells to deal with nutrient emergency. But explosive work in the last 15 years has given increasingly new knowledge to our understanding of this process. Many of the functions of autophagy that are unveiled from recent studies, however, cannot be reconciled with this conventional view of cell survival but, instead, point to autophagy being integrally involved at a deeper level of cell biology, playing a critical role in maintaining homeostasis and promoting an integrated stress/immune response. The new appreciation of the role of autophagy in the evolutionary trajectory of cancer and cancer interaction with the immune system provides a mechanistic framework for understanding the clinical benefits of autophagy-based therapies. Here, we examine current knowledge of the mechanisms and functions of autophagy in highly plastic and aggressive melanoma as a model disease of human malignancy, while highlighting emerging dimensions indicating that autophagy is at play beyond its classical face.<b>Abbreviation:</b> AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ATF4: activating transcription factor 4; ATG: autophagy related; BRAF: B-Raf proto-oncogene, serine/threonine kinase; CAFs: cancer-associated fibroblasts; CCL5: C-C motif chemokine ligand 5; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTLA4: cytotoxic T-lymphocyte associated protein 4; CTL: cytotoxic T lymphocyte; DAMPs: danger/damage-associated molecular patterns; EGFR: epidermal growth factor receptor; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; FITM2: fat storage inducing transmembrane protein 2; HCQ: hydroxychloroquine; ICB: immune checkpoint blockade; ICD: immunogenic cell death; LDH: lactate dehydrogenase; MAPK: mitogen-activated protein kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; NDP52: nuclear dot protein 52; NFKB/NF-κ B: nuclear factor kappa B; NBR1: the neighbor of BRCA1; NK: natural killer; NRF1: nuclear respiratory factor 1; NSCLC: non-small-cell lung cancer; OPTN: optineurin; PDAC: pancreatic ductal adenocarcinoma; PDCD1/PD-1: programmed cell death 1; PPT1: palmitoyl-protein thioesterase 1; PTEN: phosphatase and tensin homolog; PTK2/FAK1: protein tyrosine kinase 2; RAS: rat sarcoma; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TAX1BP1: Tax1 binding protein 1; TFEB: transcription factor EB; TGFB/TGF-β: transforming growth factor beta; TMB: tumor mutational burden; TME: tumor microenvironment; TSC1: TSC complex subunit 1; TSC2: TSC complex subunit 2; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144830","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":"TP53INP2-dependent activation of muscle autophagy ameliorates sarcopenia and promotes healthy aging.","authors":"David Sebastián, Marc Beltrà, Andrea Irazoki, David Sala, Pilar Aparicio, Cecilia Aris, Esmaeil Alibakhshi, Maria Rubio-Valera, Manuel Palacín, Juan Castellanos, Luis Lores, Antonio Zorzano","doi":"10.1080/15548627.2024.2333717","DOIUrl":"10.1080/15548627.2024.2333717","url":null,"abstract":"<p><p>Sarcopenia is a major contributor to disability in older adults, and thus, it is key to elucidate the mechanisms underlying its development. Increasing evidence suggests that impaired macroautophagy/autophagy contributes to the development of sarcopenia. However, the mechanisms leading to reduced autophagy during aging remain largely unexplored, and whether autophagy activation protects from sarcopenia has not been fully addressed. Here we show that the autophagy regulator TP53INP2/TRP53INP2 is decreased during aging in mouse and human skeletal muscle. Importantly, chronic activation of autophagy by muscle-specific overexpression of TRP53INP2 prevents sarcopenia and the decline of muscle function in mice. Acute re-expression of TRP53INP2 in aged mice also improves muscle atrophy, enhances mitophagy, and reduces ROS production. In humans, high levels of TP53INP2 in muscle are associated with increased muscle strength and healthy aging. Our findings highlight the relevance of an active muscle autophagy in the maintenance of muscle mass and prevention of sarcopenia.<b>Abbreviation</b>: ATG7: autophagy related 7; BMI: body mass index; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ROS: reactive oxygen species; TP53INP2: tumor protein p53 inducible nuclear protein 2; WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140308276","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":"Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model.","authors":"Juan Yi, He-Ling Wang, Guang Lu, Hailong Zhang, Lina Wang, Zhen-Yu Li, Liming Wang, Yihua Wu, Dajing Xia, Evandro F Fang, Han-Ming Shen","doi":"10.1080/15548627.2024.2383145","DOIUrl":"10.1080/15548627.2024.2383145","url":null,"abstract":"<p><p>Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) in a PINK-1-PDR-1-dependent manner. Functionally, spautin-1 is capable of improving associative learning capability in an Alzheimer disease (AD) <i>C. elegans</i> model. In summary, we report a novel function of spautin-1 in promoting mitophagy via the PINK1-PRKN pathway. As deficiency of mitophagy is closely implicated in the pathogenesis of neurodegenerative disorders, the pro-mitophagy function of spautin-1 might suggest its therapeutic potential in neurodegenerative disorders such as AD.<b>Abbreviations:</b> AD, Alzheimer disease; ATG, autophagy related; BafA1, bafilomycin A₁; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; EBSS, Earle's balanced salt; ECAR, extracellular acidification rate; GFP, green fluorescent protein; IA, isoamyl alcohol; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MMP, mitochondrial membrane potential; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; O/A, oligomycin-antimycin; OCR, oxygen consumption rate; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; p-Ser65-Ub, phosphorylation of Ub at Ser65; TIMM23, translocase of inner mitochondrial membrane 23; TOMM, translocase of outer mitochondrial membrane; USP10, ubiquitin specific peptidase 10; USP13, ubiquitin specific peptidase 13; VAL, valinomycin; YFP, yellow fluorescent protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763193","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 mammalian actin elongation factor ENAH/MENA contributes to autophagosome formation via its actin regulatory function.","authors":"Yueheng Li, Yafei Zhang, Menghui Wang, Junhui Su, Xinjue Dong, Yuqi Yang, Hongshan Wang, QingQuan Li","doi":"10.1080/15548627.2024.2347105","DOIUrl":"10.1080/15548627.2024.2347105","url":null,"abstract":"<p><p>Macroautophagy/autophagy is a catabolic process crucial for degrading cytosolic components and damaged organelles to maintain cellular homeostasis, enabling cells to survive in extreme extracellular environments. ENAH/MENA, a member of the Ena/VASP protein family, functions as a highly efficient actin elongation factor. In this study, our objective was to explore the role of ENAH in the autophagy process. Initially, we demonstrated that depleting ENAH in cancer cells inhibits autophagosome formation. Subsequently, we observed ENAH's colocalization with MAP1LC3/LC3 during tumor cell starvation, dependent on actin cytoskeleton polymerization and the interaction between ENAH and BECN1 (beclin 1). Additionally, mammalian ATG9A formed a ring-like structure around ENAH-LC3 puncta during starvation, relying on actin cytoskeleton polymerization. Furthermore, ENAH's EVH1 and EVH2 domains were found to be indispensable for its colocalization with LC3 and BECN1, while the PRD domain played a crucial role in the formation of the ATG9A ring. Finally, our study revealed ENAH-led actin comet tails in autophagosome trafficking. In conclusion, our findings provide initial insights into the regulatory role of the mammalian actin elongation factor ENAH in autophagy.<b>Abbreviations</b>: 3-MA 3-methyladenine; ABPs actin-binding proteins; ATG autophagy related; ATG9A autophagy related 9A; Baf A1 bafilomycin A₁; CM complete medium; CytERM endoplasmic reticulum signal-anchor membrane protein; Cyto D cytochalasin D; EBSS Earl's balanced salt solution; ENAH/MENA ENAH actin regulator; EVH1 Ena/VASP homology 1 domain; EVH2 Ena/VASP homology 2 domain; GAPDH glyceraldehyde-3-phosphate dehydrogenase; Lat B latrunculin B; LC3-I unlipidated form of LC3; LC3-II phosphatidylethanolamine-conjugated form of LC3; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; mEGFP monomeric enhanced green fluorescent protein; mTagBFP2 monomeric Tag blue fluorescent protein 2; OSER organized smooth endoplasmic reticulum; PRD proline-rich domain; PtdIns3K class III phosphatidylinositol 3-kinase; WM wortmannin.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857647","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}