Autophagy最新文献

{"title":"Upregulation of ISG15 induced by MAPT/tau accumulation represses autophagic flux by inhibiting HDAC6 activity: a vicious cycle in Alzheimer disease.","authors":"Qian Liu, Xin Wang, Zhi-Ting Fang, Jun-Ning Zhao, Xue-Xiang Rui, Bing-Ge Zhang, Ye He, Rui-Juan Liu, Jian Chen, Gao-Shang Chai, Gong-Ping Liu","doi":"10.1080/15548627.2024.2431472","DOIUrl":"10.1080/15548627.2024.2431472","url":null,"abstract":"<p><p>Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models <i>in vivo</i> and <i>in vitro</i>. ISG15 overexpression in cells and the hippocampus inhibited HDAC6 (histone deacetylase 6) activity through C-terminal LRLRGG binding to HDAC6. Consequently, this increased CTTN (cortactin) acetylation, disrupted CTTN and F-actin recruitment to lysosomes, and impaired autophagosome (AP)-lysosome (LY) fusion. These disruptions led to MAPT/tau accumulation, synaptic damage, neuronal loss, and cognitive deficits. Conversely, ISG15 knockdown in our HsMAPT (human MAPT) pathology model restored HDAC6 activity, promoted AP-LY fusion, and improved cognitive function. This study identifies ISG15 as a key regulator of autophagic flux in AD, suggesting that targeting ISG15-mediated autophagy could offer therapeutic potential for AD.<b>Abbreviation</b>: AAV: adeno-associated virus; AD: Alzheimer disease; ALP: autophagy-lysosomal pathway; ANOVA: analysis of variance; AP: autophagosome; BafA1: bafilomycin A₁; CHX: cycloheximide; CQ: chloroquine; CTTN: cortactin; FC: fear conditioning; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GRIN/NMDARs: N-methyl-D-aspartate glutamate ionotropic receptor NMDA types; HDAC6: histone deacetylase 6; HEK293: human embryonic kidney 293; HsMAPT: human MAPT; IF: immunofluorescence; IHC: immunohistochemistry; IP: immunoprecipitation; ISG15: ISG15 ubiquitin like modifier; LAMP1: lysosomal associated membrane protein 1; LY: lysosome; MAPT: microtubule associated protein tau; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MWM: Morris water maze; NOR: novel object recognition; SQSTM1/p62: sequestosome 1; ZnF UBP: zinc finger ubiquitin-binding protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"807-826"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788088","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":"RHOD mediates ATG9A trafficking to promote autophagosome formation during autophagy in cancer.","authors":"Sijia Wang, Jing Ren, Jinghan Chi, Yifei Guan, Ran Zheng, Juan Wang, Xinhui Liu, Hua Huang","doi":"10.1080/15548627.2025.2484604","DOIUrl":"10.1080/15548627.2025.2484604","url":null,"abstract":"<p><p>ATG9A is a transmembrane protein essential for macroautophagy/autophagy that drives autophagosome formation by delivering essential proteins and lipids to the phagophore through vesicle trafficking. Here, we demonstrate that the atypical Rho GTPase RHOD is required for ATG9A trafficking and stimulates autophagosome formation. Upon starvation, RHOD interacted with ATG9A and accompanied ATG9A trafficking from the Golgi toward phagophores. In addition, starvation-induced high levels of RHOD resulted in Golgi fragmentation to further promote ATG9A vesicle export from the trans-Golgi network to the peripheral region. Loss of RHOD suppressed ATG9A trafficking and reduced the distribution of ATG9A on the phagophore. Moreover, WHAMM (WASP homolog associated with actin, golgi membranes and microtubules) forms a complex with RHOD and participates in this process in a RHOD-dependent manner. Importantly, RHOD mutants, which lack the exon II-containing effector region motif that is required for ATG9A binding or lack the CAAX box that is responsible for membrane targeting, fail to stimulate ATG9A trafficking and autophagosome formation. Furthermore, RHOD plays a distinct suppressor role in tumor development, partly associated with its regulatory effect on autophagy. These findings reveal the important roles of RHOD in autophagy and tumor development.<b>Abbreviation</b>: ATG9A: autophagy related 9A; BafA1: bafilomycin A₁; BiFC: bimolecular fluorescence complementation; co-IP: co-immunoprecipitation; EBSS: Earle's balanced salt solution; FM: full culture medium; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PUP-IT: pupylation-based interaction tagging; RHOD: ras homolog family member D; SQSTM1: sequestosome 1; TGN: trans-Golgi network; VC: Venus C-terminal; VN: Venus N-terminal; WHAMM: WASP homolog associated with actin, golgi membranes and microtubules; WIPI2: WD repeat domain, phosphoinositide interacting 2; WT: wild-type; 3-MA: phosphatidylinositol 3-kinase (PtdIns3K) inhibitor 3-methyladenine.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722986","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":"Chaperone-mediated autophagy degrades SERPINA1^E342K/α1-antitrypsin Z variant and alleviates cell stress.","authors":"Jiayu Lin, Xinyue Wei, Yan Dai, Haorui Lu, Yajian Song, Jiansong Ju, Rihan Wu, Qichen Cao, Hao Yang, Lang Rao","doi":"10.1080/15548627.2025.2480037","DOIUrl":"10.1080/15548627.2025.2480037","url":null,"abstract":"<p><p>Chaperone-mediated autophagy (CMA) is a specific form of autophagy that selectively targets proteins containing a KFERQ-like motif and relies on the chaperone protein HSPA8/HSC70 for substrate recognition. In SERPINA1/a1-antitrypsin deficiency (AATD), a disease characterized by the hepatic buildup of the SERPINA1^E342K/ATZ, CMA's role had been unclear. This work demonstrates the critical role that CMA plays in preventing SERPINA1^E342K/ATZ accumulation; suppressing CMA worsens SERPINA1^E342K/ATZ accumulation while activating it through chemical stimulation or LAMP2A overexpression promotes SERPINA1^E342K/ATZ breakdown. Specifically, SERPINA1^E342K/ATZ's ₁₂₁QELLR₁₂₅ motif is critical for HSPA8/HSC70 recognition and LAMP2A's charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of SERPINA1^E342K/ATZ. This selective activation of CMA operates independently of other autophagy pathways and alleviates SERPINA1^E342K/ATZ aggregate-induced cellular stress. In vivo administration of AR7 promotes hepatic SERPINA1^E342K/ATZ elimination and mitigates hepatic SERPINA1^E342K/ATZ aggregation pathology. These findings highlight CMA's critical function in cellular protein quality control of SERPINA1^E342K/ATZ and place it as a novel target for AATD treatment.<b>Abbreviation:</b> AR7: atypical retinoid 7; ATG16L1: autophagy related 16 like 1; AATD: SERPINA1/alpha-1 antitrypsin deficiency; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; MG132: carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; PAS-D: periodic acid-Schiff plus diastase; SERPINA1/A1AT: serpin family A member 1; SERPINA1^E342K/ATZ: Z variant of SERPINA1; TMRE: tetramethyl rhodamine ethyl ester perchlorate.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671496","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-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis.","authors":"Mariella Arcos, Lavanya Goodla, Hyeoncheol Kim, Sharina P Desai, Rui Liu, Kunlun Yin, Zhaoli Liu, David R Martin, Xiang Xue","doi":"10.1080/15548627.2024.2425594","DOIUrl":"10.1080/15548627.2024.2425594","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Mitophagy, the process by which cells eliminate damaged mitochondria, is mediated by PINK1 (PTEN induced kinase 1). Our recent research indicates that PINK1 functions as a tumor suppressor in colorectal cancer by regulating cellular metabolism. Interestingly, PINK1 ablation activated the NLRP3 (NLR family pyrin domain containing 3) inflammasome, releasing IL1B (interleukin 1 beta). However, inhibiting the NLRP3-IL1B signaling pathway with an IL1R (interleukin 1 receptor) antagonist or NLRP3 inhibitor did not hinder colon tumor growth after PINK1 loss. To identify druggable targets in PINK1-deficient tumors, ribonucleic acid sequencing analysis was performed on colon tumors from &lt;i&gt;pink1&lt;/i&gt; knockout and wild-type mice. Gene Set Enrichment Analysis highlighted the enrichment of iron ion transmembrane transporter activity. Subsequent qualitative polymerase chain reaction and western blot analysis revealed an increase in mitochondrial iron transporters, including mitochondrial calcium uniporter, in PINK1-deficient colon tumor cells and tissues. Live-cell iron staining demonstrated elevated cellular and mitochondrial iron levels in PINK1-deficient cells. Clinically used drugs deferiprone and minocycline reduced mitochondrial iron and superoxide levels, resulting in decreased colon tumor cell growth &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;. Manipulating the mitochondrial iron uptake protein MCU (mitochondrial calcium uniporter) also affected cell and xenograft tumor growth. This study suggests that therapies aimed at reducing mitochondrial iron levels may effectively inhibit colon tumor growth, particularly in patients with low PINK1 expression.&lt;b&gt;Abbreviation&lt;/b&gt;: ANOVA: analysis of variance; APC: adenomatous polyposis coli; cAMP: cyclic adenosine monophosphate; CDX2: caudal type homeobox 2; CGAS: cyclic GMP-AMP synthase; CRC: colorectal cancer; DNA: deoxyribonucleic acid; DFP: deferiprone; DMEM: Dulbecco's modified Eagle medium; DSS: dextran sodium sulfate; ERT2-Cre: Cre recombinase fused to a triple mutant form of the human estrogen receptor; EV: empty vector; GLB: glybenclamide/glyburide; H&E: hematoxylin and eosin; ICP-MS: inductively coupled plasma mass spectrometer; IL1B: interleukin 1 beta; kDa: kilodalton; MCU: mitochondrial calcium uniporter; MKI67: marker of proliferation Ki-67; mRNA: messenger ribonucleic acid; MTT: 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide; NLRP3: NLR family pyrin domain containing 3; OE: overexpression; PBS: phosphate-buffered saline; p-CREB: phosphorylated cAMP responsive element binding protein; PINK1: PTEN induced kinase 1; p-PRKAA/AMPK: phosphorylated protein kinase AMP-activated catalytic subunit alpha; qPCR: qualitative polymerase chain reaction; RNA-seq: ribonucleic acid sequencing; ROS: reactive oxygen species; sg: single guide; sh: short hairpin; SLC25A28: solute carrier family 25 member 28; SLC25A37/MFRN: solute carrier family 25 member 37; STING1: stimulator of interferon response cGAMP inte","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"737-753"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607142","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 alpha-coronavirus E protein inhibits the JAK-STAT pathway signaling by triggering STAT2 degradation through OPTN- and NBR1-mediated selective autophagy.","authors":"Zhao Huang, Chenyang Gao, Shaohong Huang, Sizhan Lin, WenBo Zhang, Jianyi You, Xiongnan Chen, Pei Zhou, Guihong Zhang, Lang Gong","doi":"10.1080/15548627.2025.2479671","DOIUrl":"10.1080/15548627.2025.2479671","url":null,"abstract":"<p><p>The zoonotic transmission of coronaviruses continues to pose a considerable threat to humans. Swine acute diarrhea syndrome coronavirus (SADS-CoV), a bat coronavirus related to HKU2, causes severe economic losses in the pig industry and has the potential to trigger outbreaks in humans. However, our understanding of how SADS-CoV evades the host's innate immunity remains limited, hindering effective responses to potential human outbreaks. In this study, we demonstrate that the SADS-CoV envelope protein (E) inhibits type I interferon (IFN-I) signaling by inducing the degradation of STAT2 via the macroautophagy/autophagy-lysosome pathway. Mechanistically, the E protein evades host innate immunity by promoting STAT2 degradation through autophagy, mediated by the NBR1 and OPTN receptors. Notably, ubiquitination of E protein is required for the autophagic degradation of STAT2. Additionally, lysine residue K61 of the E protein is crucial for its stable expression; however, it is not involved in its ubiquitination. In conclusion, our study reveals a novel mechanism by which the E protein disrupts IFN-I signaling by targeting STAT2 via autophagy, enhancing our understanding of SADS-CoV's immune evasion strategies and providing potential drug targets for controlling viral infections.<b>Abbreviations</b>: 3-MA: 3-methyladenine; ATG: autophagy related; BafA1: bafilomycin A₁; BSA: bovine serum albumin; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CC: coiled-coil; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; DBD: DNA-binding domain; DMEM: Dulbecco's Modified Eagle's medium; DMSO: dimethyl sulfoxide; E, Envelope. FW: four-tryptophan; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HA: hemagglutinin; hpt: hours post-treatment; IF: indirect immunofluorescence; IFNB/IFN-β: interferon beta; IgG: immunoglobulin G; ISG: IFN-stimulated genes; ISRE: interferon-stimulated response element; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PBS: phosphate-buffered saline; PRRs: pattern recognition receptors; qPCR: quantitative polymerase chain reaction; SAR: selective autophagy receptor; SQSTM1/p62: sequestosome 1; STAT: signal transduction and activator of transcription; TBS-T: Tris-buffered saline with Tween 20; TCID50: 50% tissue culture infective dose; TOLLIP: toll interacting protein; Ub: ubiquitin; UBA: C-terminal ubiquitin-associated; VSV: vesicular stomatitis virus; WB: western blotting. WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652615","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":"ADSL-produced fumarate increases BECN1 dimethylation to promote autophagy and liver tumor growth.","authors":"Lei Wang, Guimei Ji, Yuran Duan, Peixiang Zheng, Zhiqiang Hu, Zheng Wang, Daqian Xu","doi":"10.1080/15548627.2025.2481125","DOIUrl":"10.1080/15548627.2025.2481125","url":null,"abstract":"<p><p>Cancer cells depend on the reprogramming of cell metabolism to constantly adapt metabolically to the tumor microenvironment. ADSL (adenylosuccinate lyase), a rate-limiting enzyme in de novo purine synthesis, is overexpressed in various cancer cells. However, whether ADSL functions in other oncogenic signaling is largely unknown. Here, our recent study shows that ADSL interacts with BECN1 (beclin 1) to regulate macroautophagy/autophagy upon lipid deprivation. Mechanistically, ADSL is phosphorylated at S140 by EIF2AK3/PERK (eukaryotic translation initiation factor 2 alpha kinase 3) in response to lipid deprivation, which enhances the association between ADSL and BECN1. ADSL-produced fumarate reduces the BECN1-associated KDM8 activity, leading to increased BECN1 K117 dimethylation. BECN1 K117 dimethylation inhibits its interaction with BCL2 to initiate autophagy. Targeting the ADSL-BECN1 axis by knock-in mutation or a cell-penetrating peptide inhibits autophagy and blunts liver tumor growth in mice. These findings broaden the physiological significance of ADSL in autophagy and liver tumor development.<b>Abbreviation</b>: α-KG: alpha-ketoglutarate; ADSL: adenylosuccinate lyase; AMP: adenosine monophosphate; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; HCC: hepatocellular carcinoma; KDM8: lysine demethylase 8; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ULK1: unc-51 like autophagy activating kinase 1; WIPI2: WD repeat domain, phosphoinositide interacting 2.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660088","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":"Keeping your endosymbiont under control: the enigmatic plastid membrane ATG8ylation in Apicomplexa parasites.","authors":"Sébastien Besteiro","doi":"10.1080/15548627.2025.2483445","DOIUrl":"10.1080/15548627.2025.2483445","url":null,"abstract":"<p><p>ATG8ylation of membranes has been increasingly reported over the last few years, in various configurations and across different eukaryotic models. While the unconventional conjugation of ATG8 to the outermost membrane of the plastid in apicomplexan parasites was first observed over a decade ago, it is often overlooked in literature reviews focusing on the ATG8ylation of non-autophagosomal membranes. Here, I provide a brief overview of the current knowledge on plastid ATG8ylation in these parasites and discuss a possible parallel between the evolutionary origin of this plastid and other ATG8ylation processes, such as LC3-associated phagocytosis.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-5"},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694765","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 Whi2-Psr1-Psr2 complex selectively regulates TORC1 and autophagy under low leucine conditions but not nitrogen depletion.","authors":"Yitao Wang, Yang Ping, Rui Zhou, Guiqin Wang, Yu Zhang, Xueyu Yang, Mingjun Zhao, Dongsheng Liu, Madhura Kulkarni, Heather Lamb, Qingwei Niu, J Marie Hardwick, Xinchen Teng","doi":"10.1080/15548627.2025.2481014","DOIUrl":"10.1080/15548627.2025.2481014","url":null,"abstract":"<p><p>Amino acids and ammonia serve as sources of nitrogen for cell growth and were previously thought to have similar effects on yeast. Consistent with this idea, depletion of either of these two nitrogen sources inhibits the target of rapamycin complex 1 (TORC1), leading to induction of macroautophagy/autophagy and inhibition of cell growth. In this study, we show that Whi2 and the haloacid dehalogenase (HAD)-type phosphatases Psr1 and Psr2 distinguish between these two nitrogen sources in <i>Saccharomyces cerevisiae</i>, as the Whi2-Psr1-Psr2 complex inhibits TORC1 in response to low leucine but not in the absence of nitrogen. In contrast, a parallel pathway controlled by Npr2 and Npr3, components of the Seh1-associated complex inhibiting TORC1 (SEACIT), suppress TORC1 under both low leucine- and nitrogen-depletion conditions. Co-immunoprecipitations with mutants of Whi2, Psr1, Psr2 and fragments of Tor1 support the model that Whi2 recruits Psr1 and Psr2 to TORC1. In accordance, the interaction between Whi2 and Tor1 appears to increase under low leucine but decreases under nitrogen-depletion conditions. Although the targets of Psr1 and Psr2 phosphatases are not known, mutation of their active sites abolishes their inhibitory effects on TORC1. Consistent with the conservation of HAD phosphatases across species, human HAD phosphatases CTDSP1 (CTD small phosphatase 1), CTDSP2, and CTDSPL can functionally replace Psr1 and Psr2 in yeast, restoring TORC1 inhibition and autophagy activation in response to low leucine conditions.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660123","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":"H3K36me2 methyltransferase NSD2/WHSC1 promotes triple-negative breast cancer metastasis via activation of ULK1-dependent autophagy.","authors":"Danyang Chen, Xiaohui Chen, Mingqiang Yang, Qiunuo Li, Shaojuan Weng, Siyue Kou, Xi Liu, Guanmin Jiang, Hao Liu","doi":"10.1080/15548627.2025.2479995","DOIUrl":"10.1080/15548627.2025.2479995","url":null,"abstract":"<p><p>Metastasis is the primary cause for treatment failure and poor prognosis in patients with triple-negative breast cancer (TNBC). Macroautophagy/autophagy plays a crucial role in tumor growth and metastasis. Genetic or epigenetic regulation of autophagy-related factors alters autophagy levels, which subsequently promotes cancer progression and affects the therapeutic effectiveness. However, the molecular basis for the transcriptional and epigenetic regulation of autophagy in TNBC progression is poorly understood. In this study, we reveal the histone methyltransferase NSD2/WHSC1 (nuclear receptor binding SET domain protein 2) as a novel epigenetic regulator of autophagy in TNBC progression. We demonstrate that the expression of NSD2 is significantly upregulated in TNBC cells and high NSD2 expression is correlated with poor TNBC survival. Elevated expression of NSD2 significantly promotes TNBC metastasis in multiple TNBC models. Mechanistically, ULK1 (unc-51 like autophagy activating kinase 1) is identified as a novel target of NSD2 and NSD2-mediated histone H3K36me2 methylation directly activates ULK1 transcription in TNBC cells. Notably, NSD2-induced ULK1 expression facilitates autophagosome maturation and increases autophagic flux, thus promoting autophagy-related malignancy progression in TNBC. Furthermore, pharmacological inhibition of NSD2 using MS159 and MCTP-39 significantly suppresses TNBC autophagy, growth, and metastasis both <i>in vivo</i> and <i>in vitro</i>. In conclusion, our findings demonstrate a pivotal epigenetic role for the NSD2-H3K36me2 axis in regulating ULK1 expression and identify a novel NSD2-ULK1-autophagy signaling axis in the promotion of TNBC progression, suggesting that NSD2 inhibition may be an effective treatment strategy for TNBC.<b>Abbreviations</b>: CDH2/N-cadherin: cadherin 2; ChIP: chromatin immunoprecipitation; EMT: epithelial-mesenchymal transition; ESR: estrogen receptor; FN1: fibronectin 1; GEPIA: Gene Expression Profiling Interactive Analysis; H3K36me2: di-methylation at lysine 36 of histone 3; H&E: hematoxylin and eosin; HDM: histone demethylase; HMT: histone methyltransferase; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; IF: Immunofluorescence; IHC: Immunohistochemistry; NSD: nuclear receptor binding SET domain protein; PGR: progesterone receptor; qRT-PCR: quantitative RT-PCR; TCGA: The Cancer Genome Atlas; TNBC: triple-negative breast cancer; TSS: transcription start site; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652612","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 TBK1-SCF^FBXO3-TMEM192-TAX1BP1 axis: a novel regulatory mechanism for lysophagy.","authors":"Na Yeon Park, Dong-Hyung Cho","doi":"10.1080/15548627.2025.2479669","DOIUrl":"10.1080/15548627.2025.2479669","url":null,"abstract":"<p><p>Lysophagy, the selective macroautophagic/autophagic clearance of damaged lysosomes, is a critical mechanism for maintaining cellular homeostasis. Our recent study identified a novel regulatory axis involving TBK1, SCF^FBXO3, TMEM192, and TAX1BP1 that orchestrates lysophagic flux following lysosomal damage. We demonstrated that TBK1-dependent phosphorylation of FBXO3 facilitates its interaction with TMEM192, promoting its ubiquitination and subsequent recognition by the autophagy receptor TAX1BP1. Perturbing this pathway significantly reduces lysophagic flux and results in accumulation of damaged lysosomes. These findings establish a previously unrecognized mechanistic link between ubiquitination, receptor recruitment, and lysophagic degradation, broadening our understanding of lysosomal quality control.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626860","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}