Autophagy最新文献

{"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":"<p><p>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-2^ORF3a, 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.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1390-1392"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","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}

{"title":"<i>Salmonella</i> Typhimurium persistently infects host via its effector SseJ-induced PHB2-mediated mitophagy.","authors":"Dage Sun, Hongchao Gou, Yu Zhang, Jiayi Li, Changzhi Dai, Haiyan Shen, Kaifeng Chen, Yu Wang, Peng Pan, Ting Zhu, Chenggang Xu, Tongling Shan, Ming Liao, Jianmin Zhang","doi":"10.1080/15548627.2025.2462511","DOIUrl":"10.1080/15548627.2025.2462511","url":null,"abstract":"<p><p>Despite decades of research on effective methods to resist <i>Salmonella enterica</i> serovar Typhimurium (<i>S</i>. Typhimurium) pathogenicity, the mechanisms of <i>S</i>. Typhimurium-host interactions have not been fully determined. <i>S</i>. Typhimurium is characterized as an important zoonosis in public health worldwide because of its endemicity, high morbidity, and difficulty in applying control and prevention measures. Herein, we introduce a novel bacterial factor, secretion system effector J (SseJ), and its interactive host protein, PHB2 (prohibitin 2). We explored whether SseJ affected <i>S</i>. Typhimurium replication and survival in the host. <i>S</i>. Typhimurium infection caused severe mitochondrial damage and mitophagy, which facilitated <i>S</i>. Typhimurium proliferation in cells. <i>S</i>. Typhimurium SseJ activated the PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase)-autophagosome-dependent mitophagy pathway, aided by the mitophagy receptor PHB2, for bacterial survival and persistent infection. Moreover, suppression of mitophagy alleviated the pathogenicity of <i>S</i>. Typhimurium. In conclusion, <i>S</i>. Typhimurium infection could be antagonized by targeting the SseJ-PHB2-mediated host mitochondrial autophagy pathway.<b>Abbreviation</b>: ACTB: actin beta; BafA1: bafilomycin A₁; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; co-IP: co-immunoprecipitation; CFU: colony-forming units; COX4/COXIV: cytochrome c oxidase subunit 4; CQ: chloroquine; hpi: h post-bacterial infection; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1:mitophagy inhibitor mitochondrial division inhibitor 1; MFN2: mitofusin 2; MG132: z-leu-leu-leucinal; MOI: multiplicity of infection; mtDNA: mitochondrial DNA; PBS: phosphate-buffered saline; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; qPCR: quantitative real-time reverse transcription PCR; Roc-A: Rocaglamide A; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; SCVs: <i>Salmonell</i>a-containing vacuoles; siRNA: small interfering RNA; SPI-2: <i>Salmonella</i> pathogenicity island 2; SseJ: secretion system effector J; <i>S</i>. Typhimurium: <i>Salmonella enterica</i> serovar Typhimurium; <i>S</i>.T-<i>ΔSseJ</i>: SseJ gene-deleted <i>Salmonella</i> Typhimurium strains; <i>S</i>.T-<i>CΔSseJ</i>: SseJ-complemented <i>Salmonella</i> Typhimurium strains; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1228-1244"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191530","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":"Scrambling stem cell development: VMP1 and TMEM41B regulate FZD2/FRIZZLED2 secretion during primitive endoderm specification.","authors":"Markus Holzner, Giulio Di Minin","doi":"10.1080/15548627.2025.2468483","DOIUrl":"10.1080/15548627.2025.2468483","url":null,"abstract":"<p><p>The endoplasmic reticulum (ER) is a central hub for lipid metabolism and protein secretion, crucial for maintaining cellular homeostasis and mediating environmental interactions. ER-resident proteins VMP1 and TMEM41B function as scramblases, regulating lipid membranes to support macroautophagy and lipid droplet metabolism. To explore their developmental roles, we generated <i>Vmp1</i> and <i>Tmem41b</i> mutations in mouse embryonic stem cells (ESCs). While these mutations did not affect ESC self-renewal or pluripotency, they impaired differentiation into the primitive endoderm lineage. Our findings reveal that this defect stems from VMP1 and TMEM41B's critical role in the maturation and stability of FZD2/FRIZZLED2, essential for WNT signaling. Thus, this study highlights their extensive role in protein trafficking, linking lipid metabolism to cell signaling and deepening our understanding of their diverse contributions to cellular and developmental processes.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1384-1386"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451316","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":"Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle.","authors":"Han Dong, Yifan Lyu, Chien-Yung Huang, Shih-Yin Tsai","doi":"10.1080/15548627.2025.2457925","DOIUrl":"10.1080/15548627.2025.2457925","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Postmitotic skeletal muscle critically depends on tightly regulated protein degradation to maintain proteomic stability. Impaired macroautophagy/autophagy-lysosomal or ubiquitin-proteasomal protein degradation causes the accumulation of damaged proteins, ultimately accelerating muscle dysfunction with age. While &lt;i&gt;in vitro&lt;/i&gt; studies have demonstrated the complementary nature of these systems, their interplay at the organism levels remains poorly understood. Here, our study reveals novel insights into this complex relationship in autophagy-deficient skeletal muscle. We demonstrated that despite a compensatory increase in proteasome level in response to autophagy impairment, 26S proteasome activity was not proportionally enhanced in autophagy-deficient skeletal muscle. This functional deficit was partly attributed to reduced ATP levels to fuel the 26S proteasome. Remarkably, we found that activation of EIF4EBP1, a crucial inhibitor of cap-dependent translation, restored and even augmented proteasomal function through dual mechanisms. First, genetically activating EIF4EBP1 enhanced both ATP-dependent 26S proteasome and ATP-independent 20S proteasome activities, thereby expanding overall protein degradation capacity. Second, EIF4EBP1 activation caused muscle fiber transformation and increased mitochondrial biogenesis, thus replenishing ATP levels for 26S proteasome activation. Notably, the improved performance of the 20S proteasome in EIF4EBP1-activated skeletal muscle was attributed to an increased abundance of the immunoproteasome, a subtype specially adapted to function under oxidative stress conditions. This dual action of EIF4EBP1 activation preserved proteomic integrity in autophagy-deficient skeletal muscle. Our findings uncover a novel role of EIF4EBP1 in improving protein quality control, presenting a promising therapeutic strategy for autophagy-related muscular disorders and potentially other conditions characterized by proteostatic imbalance.&lt;b&gt;Abbreviations&lt;/b&gt;: 3-MA: 3-methyladenine; ACAC/ACC: acetyl-Coenzyme A carboxylase; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATP: adenosine triphosphate; ATP5F1A/ATP5A: ATP synthase F1 subunit alpha; CKM-Cre: creatine kinase, muscle-Cre; CMA: chaperone-mediated autophagy; CTSB: cathepsin B; CTSK: cathepsin K; CTSL: cathepsin L; CUL3: cullin 3; EDL: extensor digitorum longus; EIF4E: eukaryotic translation initiation factor 4E; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EIF4F: eukaryotic translation initiation factor 4F complex; FBXO32/ATROGIN1/MAFbx: F-box protein 32; GFP: green fluorescent protein; IFNG/IFN-γ: interferon gamma; KEAP1: kelch-like ECH-associated protein 1; LAMP1: lysosomal-associated membrane protein 1; LAMP2: lysosomal-associated membrane protein 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; &lt;i&gt;Myl1/Mlc1f&lt;/i&gt;-Cre: myosin, light polypeptide 1 (promo","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1212-1227"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061560","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":"Correction.","authors":"","doi":"10.1080/15548627.2025.2486869","DOIUrl":"10.1080/15548627.2025.2486869","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"x-xiii"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782238","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":"Correction.","authors":"","doi":"10.1080/15548627.2023.2260140","DOIUrl":"10.1080/15548627.2023.2260140","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"vii"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41160364","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":"<i>Mycobacterium bovis</i> Mb3523c protein regulates host ferroptosis via chaperone-mediated autophagy.","authors":"Haoran Wang, Dingpu Liu, Xin Ge, Yuanzhi Wang, Xiangmei Zhou","doi":"10.1080/15548627.2025.2468139","DOIUrl":"10.1080/15548627.2025.2468139","url":null,"abstract":"<p><p>The occurrence of necrosis during <i>Mycobacterium bovis</i> (<i>M. bovis</i>) infection is regarded as harmful to the host because it promotes the spread of <i>M. bovis</i>. Ferroptosis is a controlled type of cell death that occurs when there is an excessive buildup of both free iron and harmful lipid peroxides. Here, we demonstrate that the mammalian cell entry (Mce) 4 family protein Mb3523c triggers ferroptosis to promote <i>M. bovis</i> pathogenicity and dissemination. Mechanistically, Mb3523c, through its Y237 and G241 site, interacts with host HSP90 protein to stabilize the LAMP2A on the lysosome to promote the chaperone-mediated autophagy (CMA) pathway. Then, GPX4 is delivered to lysosomes for destruction via the CMA pathway, eventually inducing ferroptosis to promote <i>M. bovis</i> transmission. In summary, our findings offer novel insights into the molecular mechanisms of pathogen-induced ferroptosis, demonstrating that targeting the GPX4-dependent ferroptosis through blocking the <i>M. bovis</i> Mb3523c-host HSP90 interface represents a potential therapeutic strategy for tuberculosis (TB).<b>Abbreviations</b>: CFU: colony-forming units; CMA: chaperone-mediated autophagy; Co-IP: co-immunoprecipitation; Fer-1: ferrostatin-1; GPX4: glutathione peroxidase 4; HSP90: heat shock protein 90; LDH: lactate dehydrogenase; Mce: mammalian cell entry; MOI: multiplicity of infection; Nec-1: necrostatin-1; PI: propidium iodide; RCD: regulated cell death.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1335-1352"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451313","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":"Heat-shock chaperone HSPB1 mitigates poly-glycine-induced neurodegeneration via restoration of autophagic flux.","authors":"Ning Ding, Yijie Song, Yuhang Zhang, Wei Yu, Xinnan Li, Wei Li, Lei Li","doi":"10.1080/15548627.2025.2466144","DOIUrl":"10.1080/15548627.2025.2466144","url":null,"abstract":"<p><p>The CGG repeat expansions in the 5'-UTR regions of certain genes have been implicated in various neurodegenerative and muscular disorders. However, the underlying pathogenic mechanisms are not well understood. In this study, we explore the role of the small molecular chaperone HSPB1 in counteracting neurodegeneration induced by poly-glycine (poly-G) aggregates. Employing a reporter system, we demonstrate that CGG repeat expansions within the 5'-UTR of the <i>GIPC1</i> gene produce poly-G proteins, by repeat-associated non-AUG (RAN) translation. Through proximity labeling and subsequent mass spectrometry analysis, we characterize the composition of poly-G insoluble aggregates and reveal that these aggregates sequester key macroautophagy/autophagy receptors, SQSTM1/p62 and TOLLIP. This sequestration disrupts MAP1LC3/LC3 recruitment and impairs autophagosome formation, thereby compromising the autophagic pathway. Importantly, we show that HSPB1 facilitates the dissociation of these receptors from poly-G aggregates and consequently restores autophagic function. Overexpressing HSPB1 alleviates poly-G-induced neurodegeneration in mouse models. Taken together, these findings highlight a mechanistic basis for the neuroprotective effects of HSPB1 and suggest its potential as a therapeutic target in treating poly-G-associated neurodegenerative diseases.<b>Abbreviations</b>: AD: Alzheimer disease; AIF1/Iba1: allograft inflammatory factor 1; Baf A₁: bafilomycin A₁; BFP: blue fluorescent protein; CQ: chloroquine; EIF2A/eIF-2α: eukaryotic translation initiation factor 2A; FRAP: fluorescence recovery after photobleaching; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GFP: green fluorescent protein; HSPB1: heat shock protein family B (small) member 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; NOTCH2NLC: notch 2 N-terminal like C; PD: Parkinson disease; PFA: paraformaldehyde; poly-A: poly-alanine; poly-G: poly-glycine; poly-R: poly-arginine; RAN translation: repeat-associated non-AUG translation; RBFOX3/NeuN: RNA binding fox-1 homolog 3; STED: stimulated emission depletion; TARDBP/TDP-43: TAR DNA binding protein; TG: thapsigargin; TOLLIP: toll interacting protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1298-1315"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401012","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":"Phosphorylation of BCL2L13 by PRKAA2/AMPKα2 activates mitophagy in pressure-overloaded heart.","authors":"Tomokazu Murakawa, Kinya Otsu","doi":"10.1080/15548627.2025.2465408","DOIUrl":"10.1080/15548627.2025.2465408","url":null,"abstract":"<p><p>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 <i>in vivo</i> role of BCL2L13 remains unclear. In this study, we investigated the cardiac function of BCL2L13 using <i>bcl2l13</i> knockout mice and knock-in mice expressing a non-phosphorylatable BCL2L13^S272A 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 <i>bcl2l13</i> and <i>prkn/parkin</i> double-knockout mice but found no additive effects of <i>prkn</i> 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.<b>Abbreviation</b>: 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.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1382-1383"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","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}

{"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":"<p><p>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 <i>in vitro</i> and <i>in vivo</i> 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 <i>Rplp1</i> (ribosomal protein lateral stalk subunit P1) gene expression. Overexpression or siRNA knockdown of <i>Esrra in vitro</i> or <i>in vivo</i> led to parallel changes in <i>Rplp1</i> 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.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1283-1297"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","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}