Autophagy最新文献_第9页

Correction.

Autophagy Pub Date : 2025-02-25 DOI: 10.1080/15548627.2025.2450891

引用次数: 0

Calcium release from damaged lysosomes triggers stress granule formation for cell survival.

Autophagy Pub Date : 2025-02-24 DOI: 10.1080/15548627.2025.2468910

Aravinth Kumar Jayabalan, Aanuoluwakiitan Ayeni, Jingyue Jia

{"title":"Calcium release from damaged lysosomes triggers stress granule formation for cell survival.","authors":"Aravinth Kumar Jayabalan, Aanuoluwakiitan Ayeni, Jingyue Jia","doi":"10.1080/15548627.2025.2468910","DOIUrl":"10.1080/15548627.2025.2468910","url":null,"abstract":"Lysosomes are essential membrane-bound organelles that integrate intracellular needs and external signals through multiple functions, including autophagy-mediated degradation and MTORC1 signaling. The integrity of the lysosomal membrane is therefore crucial for maintaining cellular homeostasis. Various endogenous and exogenous factors can damage lysosomes, contributing to diseases such as infections, cancer, and neurodegeneration. In response, cells mount defensive mechanisms to cope with such stress, including the formation of stress granules (SGs)-membrane-less organelles composed of RNAs and protein complexes. While SGs have emerged as key players in repairing damaged lysosomes, how lysosomal damage triggers their formation and influences cell fate remains unclear. Here we report that the calcium signal from damaged lysosomes mediates SG formation and protects cells from lysosomal damage-induced cell death. Mechanistically, calcium leakage from damaged lysosomes signals the recruitment of calcium-activating protein PDCD6IP/ALIX and its partner PDCD6/ALG2. This complex regulates protein kinase EIF2AK2/PKR and its activator PRKRA/PACT, which phosphorylates translation initiator factor EIF2S1, stalling global translation initiation. This translation arrest leads to the accumulation of inactive messenger ribonucleoprotein complexes (mRNPs), resulting in SG formation. Cells deficient in SG formation show increased cell death when exposed to lysosomal damage from disease-associated factors including SARS-CoV-2ORF3a, adenovirus, malarial pigment, proteopathic MAPT/tau, or environmental hazards. Collectively, this study reveals how damaged lysosomes signal through calcium to trigger SG assembly, promoting cell survival. This establishes a novel link between membrane-bound and membrane-less organelles, with implications for diseases involving lysosome and SG dysfunction.","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442707","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}

引用次数: 0

Lysosomal quality control Review.

Autophagy Pub Date : 2025-02-24 DOI: 10.1080/15548627.2025.2469206

Danielle Henn, Xi Yang, Ming Li

{"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":"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.Abbreviation: 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.","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451314","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}

引用次数: 0

Phosphorylation of BCL2L13 by PRKAA2/AMPKα2 activates mitophagy in pressure-overloaded heart.

Autophagy Pub Date : 2025-02-24 DOI: 10.1080/15548627.2025.2465408

Tomokazu Murakawa, Kinya Otsu

{"title":"Phosphorylation of BCL2L13 by PRKAA2/AMPKα2 activates mitophagy in pressure-overloaded heart.","authors":"Tomokazu Murakawa, Kinya Otsu","doi":"10.1080/15548627.2025.2465408","DOIUrl":"https://doi.org/10.1080/15548627.2025.2465408","url":null,"abstract":"In heart failure patients, the accumulation of damaged mitochondria is frequently observed in cardiomyocytes. Damaged mitochondria are degraded through mitophagy, a form of mitochondria-specific autophagy. Previously, we identified BCL2L13 as a mitophagy receptor and demonstrated its ability to induce mitophagy and mitochondrial fission in mammalian cells and the necessity of phosphorylation at Ser272 for its activation. However, the in vivo role of BCL2L13 remains unclear. In this study, we investigated the cardiac function of BCL2L13 using bcl2l13 knockout mice and knock-in mice expressing a non-phosphorylatable BCL2L13S272A mutant. In the hearts of these genetically modified mice, pressure overload leads to suppressed mitochondrial fission and mitophagy, resulting in reduced ATP production. Additionally, we analyzed bcl2l13 and prkn/parkin double-knockout mice but found no additive effects of prkn deletion. Furthermore, we identified PRKAA2/AMPKα2 as the kinase responsible for phosphorylating BCL2L13 at Ser272. These findings highlight the critical role of BCL2L13 and its phosphorylation in activating mitophagy as part of the cardiac stress response and suggest that targeting BCL2L13 phosphorylation could serve as a potential therapeutic strategy for heart failure.Abbreviation: BCL2L13, BCL2 like 13; ATG, autophagy related; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; KO, knockout; TAC, transverse aortic constriction; LVFS, left ventricular fractional shortening; ROS, reactive oxygen species; DKO, double knockout; siRNA, small interfering RNA; PRKAA2/AMPKα2, protein kinase, AMP-activated alpha 2 catalytic subunit; CCCP, carbonyl cyanide 3-chlorophenylhydrazone.","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495024","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}

引用次数: 0

Transcriptional repression of autophagy and lysosome biogenesis.

Autophagy Pub Date : 2025-02-24 DOI: 10.1080/15548627.2025.2465404

Jaebeom Kim, Young Suk Yu, Keun Il Kim, Sung Hee Baek

{"title":"Transcriptional repression of autophagy and lysosome biogenesis.","authors":"Jaebeom Kim, Young Suk Yu, Keun Il Kim, Sung Hee Baek","doi":"10.1080/15548627.2025.2465404","DOIUrl":"10.1080/15548627.2025.2465404","url":null,"abstract":"The microphthalmia/transcription factor E (MiT/TFE) family activates macroautophagy/autophagy and lysosomal genes during acute nutrient deficiency. However, the mechanisms that suppress transcription of these genes under steady-state, nutrient-rich conditions to prevent unnecessary expression remain unclear. In this study, we identified a previously unrecognized mechanism of transcriptional repression for autophagy and lysosomal genes. Under nutrient-rich conditions, USF2 (upstream transcription factor 2) binds to the coordinated lysosomal expression and regulation (CLEAR) motif, recruiting a repressive complex containing HDAC (histone deacetylase). In contrast, during nutrient deficiency, TFEB (transcription factor EB) displaces USF2 at the same motif, activating transcription. This switch is regulated by USF2 phosphorylation at serine 155 by GSK3B (glycogen synthase kinase 3 beta). Reduced phosphorylation under nutrient-deprived conditions weakens USF2's DNA binding affinity, allowing TFEB to competitively bind and activate target genes. Knockdown or knockout of Usf2 upregulates specific autophagy and lysosomal genes, leading to enhanced lysosomal functionality and increased autophagic flux. In USF2-deficient cells, the SERPINA1 Z variant/antitrypsin Z - an aggregation-prone mutant protein used as a model - is rapidly cleared via the autophagy-lysosome pathway. Therefore, modulation of USF2 activity may be a therapeutic strategy for managing diseases associated with autophagy and lysosomal dysfunction.Abbreviation: CLEAR: coordinated lysosomal expression and regulation; GSK3B: glycogen synthase kinase 3 beta; HDAC: histone deacetylase; MiT/TFE: microphthalmia/transcription factor E; NuRD: nucleosome remodeling and deacetylation; SERPINA1 Z variant/ATZ/antitrypsin Z; TFE3: transcription factor E3; TFEB: transcription factor EB; USF2: upstream transcription factor 2.","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401096","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}

引用次数: 0

Physiological insights into ESCRT-mediated phagophore closure: potential cytoprotective roles for ATG8ylated membranes.

Autophagy Pub Date : 2025-02-24 DOI: 10.1080/15548627.2025.2468907

Kouta Hamamoto, Xinwen Liang, David M Opozda, Hong-Gang Wang, Yoshinori Takahashi

{"title":"Physiological insights into ESCRT-mediated phagophore closure: potential cytoprotective roles for ATG8ylated membranes.","authors":"Kouta Hamamoto, Xinwen Liang, David M Opozda, Hong-Gang Wang, Yoshinori Takahashi","doi":"10.1080/15548627.2025.2468907","DOIUrl":"10.1080/15548627.2025.2468907","url":null,"abstract":"The endosomal sorting complex required for transport (ESCRT) machinery is a membrane abscission system that mediates various intracellular membrane remodeling processes, including macroautophagy/autophagy. In our recent study, we established the unique requirement of the ubiquitin E2 variant-like (UEVL) domain of the ESCRT-I subunit VPS37A for phagophore closure, the final step in autophagosome biogenesis, and determined the physiological impact of systemically inhibiting closure by targeting this region in mice. While the mutant mice exhibited phenotypes similar to those reported in mice deficient in generating ATG8 (mammalian Atg8 homologs)-conjugated (ATG8ylated) phagophores, certain phenotypes, such as neonatal lethality and liver injury, were found to be notably milder. Further investigation revealed that ATG8ylated phagophores promote TBK1-dependent SQSTM1 phosphorylation and droplet formation, leading to the formation of large insoluble aggregates upon closure inhibition. These findings suggest potential roles for ATG8ylated membranes in mitigating proteotoxicity by efficiently concentrating and sequestering soluble, reactive microaggregates and converting them into less reactive, insoluble large aggregates. The study highlights VPS37A UEVL mutant mice as a model for investigating the physiological and pathological roles of phagophores that extend beyond degradation.","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461067","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}

引用次数: 0

Scrambling stem cell development: VMP1 and TMEM41B regulate FZD2/FRIZZLED2 secretion during primitive endoderm specification.

Autophagy Pub Date : 2025-02-23 DOI: 10.1080/15548627.2025.2468483

Markus Holzner, Giulio Di Minin

引用次数: 0

Lysosomal Fe²⁺ influx through MCOLN1 channel prevents sustained inflammation by limiting PHDs-regulated NFKB activation in macrophages.

Autophagy Pub Date : 2025-02-19 DOI: 10.1080/15548627.2025.2465396

Meng-Meng Wang, Wuyang Wang, Jiansong Qi

{"title":"Lysosomal Fe2+ influx through MCOLN1 channel prevents sustained inflammation by limiting PHDs-regulated NFKB activation in macrophages.","authors":"Meng-Meng Wang, Wuyang Wang, Jiansong Qi","doi":"10.1080/15548627.2025.2465396","DOIUrl":"10.1080/15548627.2025.2465396","url":null,"abstract":"Lysosomes are best known for their involvement in inflammatory responses, where they participate in the macroautophagy/autophagy process to eliminate inflammasomes. Recently, we have identified a previously overlooked function of lysosomes in regulating macrophage inflammatory responses. Specifically, lysosomes finely control the production of IL1B (interleukin 1 beta) by manipulating the release of lysosomal Fe2+ through MCOLN1. Mechanistically, reactive oxygen species (ROS), accumulated during sustained inflammation in macrophages, cause activation of the MCOLN1, a lysosomal cationic channel. The activation of MCOLN1 triggers the release of lysosomal Fe2 toward the cytosol, which in turn activates prolyl hydroxylase domain enzymes (PHDs). PHDs' activation represses the transcriptional regulator NFKB/NF-kB (nuclear factor kappa B) activity by restraining RELA/p65 in the cytosol, leading to decreased IL1B transcription in macrophages. Consequently, the property of controlling production and subsequent release of IL1B from macrophages allows the lysosome to finely restrict sustained inflammatory responses. These findings demonstrate that apart from relying on its degradative capability, the lysosome also limits excessive inflammatory responses to facilitate the restoration of cellular and tissue homeostasis in macrophages by modulating the release of lysosomal Fe2+ through MCOLN1. Even more, by suppressing IL1B production, in vivo stimulation of the MCOLN1 channel alleviates multiple clinical symptoms of dextran sulfate sodium (DSS)-induced colitis in mice, highlighting MCOLN1 as a promising therapeutic target for inflammatory bowel disease (IBD) in clinical settings.","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401024","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}

引用次数: 0

Stress granules as transient reservoirs for autophagy proteins: a key mechanism for plant recovery from heat stress.

Autophagy Pub Date : 2025-02-19 DOI: 10.1080/15548627.2025.2465395

Lei Feng, Xibao Li, Wenjin Shen, Caiji Gao

{"title":"Stress granules as transient reservoirs for autophagy proteins: a key mechanism for plant recovery from heat stress.","authors":"Lei Feng, Xibao Li, Wenjin Shen, Caiji Gao","doi":"10.1080/15548627.2025.2465395","DOIUrl":"https://doi.org/10.1080/15548627.2025.2465395","url":null,"abstract":"Stress granules (SGs) are transient, non-membrane-bound cytoplasmic condensates that form in response to environmental stresses, serving as protective reservoirs for mRNAs and proteins. In plants, SGs play a crucial role in stress adaptation, but their relationship with macroautophagy/autophagy, a key process for degrading damaged organelles and misfolded proteins, remains poorly understood. In a recent study, we revealed that key autophagy proteins, including components of the ATG1-ATG13 kinase complex, the class III phosphatidylinositol 3-kinase (PtdIns3K) complex, and the ATG8-PE system, translocate to SGs during heat stress (HS) in Arabidopsis thaliana. Using biochemical, cell biological and genetic approaches, we demonstrated that ATG proteins accumulate on HS-induced SGs and are released to the cytosol upon SG disassembly during the post-HS recovery stage. This process facilitates rapid autophagy activation. Notably, a SG-deficient mutant (ubp1abc) exhibits delayed autophagy activation and impaired clearance of ubiquitinated protein aggregates, highlighting the importance of SGs in regulating autophagy. Our findings uncover a novel mechanism by which SGs sequester autophagy proteins during stress, ensuring their rapid availability for stress recovery, and provide new insights into the interplay between SGs and autophagy in plant stress responses.Abbreviation: ATG, autophagy related; HS, heat stress; PtdIns3K, phosphatidylinositol 3-kinase; RBP47B, RNA-binding protein 47B; SG, stress granule; UBP1, ubiquitin-specific protease 1.","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461071","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}

引用次数: 0

ESRRA (estrogen related receptor, alpha) induces ribosomal protein RPLP1-mediated adaptive hepatic translation during prolonged starvation.

Autophagy Pub Date : 2025-02-18 DOI: 10.1080/15548627.2025.2465183

Madhulika Tripathi, Karine Gauthier, Reddemma Sandireddy, Jin Zhou, Priyanka Gupta, Suganya Sakthivel, Nah Jiemin, Kabilesh Arul, Keziah Tikno, Sung-Hee Park, Yajun Wu, Lijin Wang, Boon-Huat Bay, Lena Ho, Vincent Giguere, Sujoy Ghosh, Donald P McDonnell, Paul M Yen, Brijesh K Singh

{"title":"ESRRA (estrogen related receptor, alpha) induces ribosomal protein RPLP1-mediated adaptive hepatic translation during prolonged starvation.","authors":"Madhulika Tripathi, Karine Gauthier, Reddemma Sandireddy, Jin Zhou, Priyanka Gupta, Suganya Sakthivel, Nah Jiemin, Kabilesh Arul, Keziah Tikno, Sung-Hee Park, Yajun Wu, Lijin Wang, Boon-Huat Bay, Lena Ho, Vincent Giguere, Sujoy Ghosh, Donald P McDonnell, Paul M Yen, Brijesh K Singh","doi":"10.1080/15548627.2025.2465183","DOIUrl":"10.1080/15548627.2025.2465183","url":null,"abstract":"Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods in vitro and in vivo to investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, ESRRA (estrogen related receptor, alpha) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating Rplp1 (ribosomal protein lateral stalk subunit P1) gene expression. Overexpression or siRNA knockdown of Esrra in vitro or in vivo led to parallel changes in Rplp1 gene expression, lysosome and macroautophagy/autophagy protein translation, and autophagy activity. Remarkably, we have found that ESRRA had dual functions by not only regulating transcription but also controlling adaptive translation via the ESRRA-RPLP1-lysosome-autophagy pathway during prolonged starvation.","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-15"},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400995","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}

引用次数: 0