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Physiological insights into ESCRT-mediated phagophore closure: potential cytoprotective roles for ATG8ylated membranes.
Pub Date : 2025-02-24 DOI: 10.1080/15548627.2025.2468907
Kouta Hamamoto, Xinwen Liang, David M Opozda, Hong-Gang Wang, Yoshinori Takahashi

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.

{"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":"<p><p>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.</p>","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
Autophagy regulates cellular senescence by mediating the degradation of CDKN1A/p21 and CDKN2A/p16 through SQSTM1/p62-mediated selective autophagy in myxomatous mitral valve degeneration.
Pub Date : 2025-02-23 DOI: 10.1080/15548627.2025.2469315
Qiyu Tang, Keyi Tang, Greg R Markby, Maciej Parys, Kanchan Phadwal, Vicky E MacRae, Brendan M Corcoran

Myxomatous mitral valve degeneration (MMVD) is one of the most important age-dependent degenerative heart valve disorders in both humans and dogs. It is characterized by the aberrant remodeling of extracellular matrix (ECM), regulated by senescent myofibroblasts (aVICs) transitioning from quiescent valve interstitial cells (qVICs), primarily under TGFB1/TGF-β1 control. In the present study, we found senescent aVICs exhibited impaired macroautophagy/autophagy as evidenced by compromised autophagy flux and immature autophagosomes. MTOR-dependent autophagy induced by rapamycin and torin-1 attenuated cell senescence and decreased the expression of cyclin-dependent kinase inhibitors (CDKIs) CDKN2A/p16INK4A and CDKN1A/p21CIP1. Furthermore, induction of autophagy in aVICs by ATG (autophagy related) gene overexpression restored autophagy flux, with a concomitant reduction in CDKN1A and CDKN2A expression and senescence-associated secretory phenotype (SASP). Conversely, autophagy deficiency induced CDKN1A and CDKN2A accumulation and SASP, whereas ATG re-expression alleviated senescent phenotypic transformation. Notably, CDKN1A and CDKN2A localized to autophagosomes and lysosomes following MTOR antagonism or MG132 treatment. SQSTM1/p62 was identified as the autophagy receptor to selectively sequester CDKN1A and CDKN2A cargoes for autophagic degradation. Our findings are the first demonstration that CDKN1A and CDKN2A are degraded through SQSTM1-mediated selective autophagy, independent of the ubiquitin-proteasome pathway. These data will inform development of therapeutic strategies for the treatment of canine and human MMVD, and for the treatment of Alzheimer disease, Parkinson disease and other age-related degenerative disorders.

肌瘤性二尖瓣变性(MMVD)是人类和狗中最重要的年龄依赖性心脏瓣膜退行性疾病之一。它的特征是细胞外基质(ECM)的异常重塑,由衰老的肌成纤维细胞(aVICs)从静止的瓣膜间质细胞(qVICs)转变而来,主要受 TGFB1/TGF-β1 的控制。在本研究中,我们发现衰老的瓣膜间充质细胞(aVICs)的大自噬/自噬功能受损,表现为自噬通量受损和自噬体不成熟。雷帕霉素和 torin-1 诱导的 MTOR 依赖性自噬减轻了细胞衰老,并降低了细胞周期蛋白依赖性激酶抑制剂(CDKIs)CDKN2A/p16INK4A 和 CDKN1A/p21CIP1 的表达。此外,通过过表达 ATG(自噬相关)基因诱导 aVIC 中的自噬,可恢复自噬通量,同时减少 CDKN1A 和 CDKN2A 的表达以及衰老相关分泌表型(SASP)。相反,自噬缺乏会诱导 CDKN1A 和 CDKN2A 的积累和 SASP,而 ATG 的再次表达则会缓解衰老表型的转变。值得注意的是,在MTOR拮抗或MG132处理后,CDKN1A和CDKN2A定位于自噬体和溶酶体。SQSTM1/p62 被鉴定为自噬受体,可选择性地扣留 CDKN1A 和 CDKN2A 货物进行自噬降解。我们的研究结果首次证明,CDKN1A 和 CDKN2A 是通过 SQSTM1 介导的选择性自噬降解的,与泛素-蛋白酶体途径无关。这些数据将为开发治疗犬和人类MMVD以及治疗阿尔茨海默病、帕金森病和其他与年龄相关的退行性疾病的治疗策略提供依据。
{"title":"Autophagy regulates cellular senescence by mediating the degradation of CDKN1A/p21 and CDKN2A/p16 through SQSTM1/p62-mediated selective autophagy in myxomatous mitral valve degeneration.","authors":"Qiyu Tang, Keyi Tang, Greg R Markby, Maciej Parys, Kanchan Phadwal, Vicky E MacRae, Brendan M Corcoran","doi":"10.1080/15548627.2025.2469315","DOIUrl":"https://doi.org/10.1080/15548627.2025.2469315","url":null,"abstract":"<p><p>Myxomatous mitral valve degeneration (MMVD) is one of the most important age-dependent degenerative heart valve disorders in both humans and dogs. It is characterized by the aberrant remodeling of extracellular matrix (ECM), regulated by senescent myofibroblasts (aVICs) transitioning from quiescent valve interstitial cells (qVICs), primarily under TGFB1/TGF-β1 control. In the present study, we found senescent aVICs exhibited impaired macroautophagy/autophagy as evidenced by compromised autophagy flux and immature autophagosomes. MTOR-dependent autophagy induced by rapamycin and torin-1 attenuated cell senescence and decreased the expression of cyclin-dependent kinase inhibitors (CDKIs) CDKN2A/p16<sup>INK4A</sup> and CDKN1A/p21<sup>CIP1</sup>. Furthermore, induction of autophagy in aVICs by <i>ATG</i> (autophagy related) gene overexpression restored autophagy flux, with a concomitant reduction in CDKN1A and CDKN2A expression and senescence-associated secretory phenotype (SASP). Conversely, autophagy deficiency induced CDKN1A and CDKN2A accumulation and SASP, whereas ATG re-expression alleviated senescent phenotypic transformation. Notably, CDKN1A and CDKN2A localized to autophagosomes and lysosomes following MTOR antagonism or MG132 treatment. SQSTM1/p62 was identified as the autophagy receptor to selectively sequester CDKN1A and CDKN2A cargoes for autophagic degradation. Our findings are the first demonstration that CDKN1A and CDKN2A are degraded through SQSTM1-mediated selective autophagy, independent of the ubiquitin-proteasome pathway. These data will inform development of therapeutic strategies for the treatment of canine and human MMVD, and for the treatment of Alzheimer disease, Parkinson disease and other age-related degenerative disorders.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484986","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
A Distinctive Form of Autophagy Induced by Oncogenic RAS.
Pub Date : 2025-02-23 DOI: 10.1080/15548627.2025.2468917
Xiaojuan Wang, Shulin Li, Min Zhang, Liang Ge

RAS mutations enhance macroautophagy/autophagy in tumor cells, crucial for their growth and survival, making autophagy a promising therapeutic target for RAS-mutant cancers. However, the distinction between RAS-induced autophagy and physiological autophagy is not well understood. We recently identified a unique form of autophagy, RAS-induced non-canonical autophagy via ATG8ylation (RINCAA), which differs from starvation-induced autophagy. RINCAA is regulated by different sets of autophagic factors and forms structures distinct from the double-membrane autophagosome known as RAS-induced multivesicular/multilaminar bodies of ATG8ylation (RIMMBA). A key feature of RINCAA is the phosphorylation of PI4KB by ULK1, and inhibiting this phosphorylation shows superior effects compared to general autophagy inhibitors. This work suggests a potential for specifically targeting autophagy in RAS-driven cancers as a therapeutic strategy.

{"title":"A Distinctive Form of Autophagy Induced by Oncogenic RAS.","authors":"Xiaojuan Wang, Shulin Li, Min Zhang, Liang Ge","doi":"10.1080/15548627.2025.2468917","DOIUrl":"https://doi.org/10.1080/15548627.2025.2468917","url":null,"abstract":"<p><p>RAS mutations enhance macroautophagy/autophagy in tumor cells, crucial for their growth and survival, making autophagy a promising therapeutic target for RAS-mutant cancers. However, the distinction between RAS-induced autophagy and physiological autophagy is not well understood. We recently identified a unique form of autophagy, RAS-induced non-canonical autophagy via ATG8ylation (RINCAA), which differs from starvation-induced autophagy. RINCAA is regulated by different sets of autophagic factors and forms structures distinct from the double-membrane autophagosome known as RAS-induced multivesicular/multilaminar bodies of ATG8ylation (RIMMBA). A key feature of RINCAA is the phosphorylation of PI4KB by ULK1, and inhibiting this phosphorylation shows superior effects compared to general autophagy inhibitors. This work suggests a potential for specifically targeting autophagy in RAS-driven cancers as a therapeutic strategy.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485029","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.
Pub Date : 2025-02-23 DOI: 10.1080/15548627.2025.2468483
Markus Holzner, Giulio Di Minin

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 Vmp1 and Tmem41b 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.

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引用次数: 0
Establishment of a yeast essential protein conditional-degradation library and screening for autophagy-regulating genes.
Pub Date : 2025-02-23 DOI: 10.1080/15548627.2025.2469189
Cong Yi, Yi Zhang, Yingcong Chen, Choufei Wu, Zhengyi Cai, Weijing Yao, Huan Yang, Juan Song, Xiankuan Xie, Liqin Zhang

Macroautophagy/autophagy is an evolutionarily conserved intracellular degradation pathway that relies on vacuoles or lysosomes. Over 40 ATG genes have been identified in yeast cells as participants in various types of autophagy, although these genes are non-essential. While some essential genes involved in autophagy have been identified using temperature-sensitive yeast strains, systematic research on essential genes in autophagy remains lacking. To address this, we established an essential protein conditional degradation library using the auxin-inducible degron (AID) system. By introducing the GFP-Atg8 plasmid, we identified 29 essential yeast genes involved in autophagy, 19 of which had not been previously recognized. In summary, the yeast essential protein conditional degradation library we constructed will serve as a valuable resource for systematically investigating the roles of essential genes in autophagy and other biological functions.

{"title":"Establishment of a yeast essential protein conditional-degradation library and screening for autophagy-regulating genes.","authors":"Cong Yi, Yi Zhang, Yingcong Chen, Choufei Wu, Zhengyi Cai, Weijing Yao, Huan Yang, Juan Song, Xiankuan Xie, Liqin Zhang","doi":"10.1080/15548627.2025.2469189","DOIUrl":"https://doi.org/10.1080/15548627.2025.2469189","url":null,"abstract":"<p><p>Macroautophagy/autophagy is an evolutionarily conserved intracellular degradation pathway that relies on vacuoles or lysosomes. Over 40 <i>ATG</i> genes have been identified in yeast cells as participants in various types of autophagy, although these genes are non-essential. While some essential genes involved in autophagy have been identified using temperature-sensitive yeast strains, systematic research on essential genes in autophagy remains lacking. To address this, we established an essential protein conditional degradation library using the auxin-inducible degron (AID) system. By introducing the GFP-Atg8 plasmid, we identified 29 essential yeast genes involved in autophagy, 19 of which had not been previously recognized. In summary, the yeast essential protein conditional degradation library we constructed will serve as a valuable resource for systematically investigating the roles of essential genes in autophagy and other biological functions.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484987","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
Autophagy induced by mechanical stress sensitizes cells to ferroptosis by the NCOA4-FTH1 axis.
Pub Date : 2025-02-23 DOI: 10.1080/15548627.2025.2469129
Chenyu Luo, Haisheng Liang, Mintao Ji, Caiyong Ye, Yiping Lin, Yuhan Guo, Zhisen Zhang, Yinyin Shu, Xiaoni Jin, Shuangshuang Lu, Wanling Lu, Yazheng Dang, Hong Zhang, Bingyan Li, Guangming Zhou, Zengli Zhang, Lei Chang

Ferroptosis is an iron-dependent regulated form of cell death implicated in various diseases, including cancers, with its progression influenced by iron-dependent peroxidation of phospholipids and dysregulation of the redox system. Whereas the extracellular matrix of tumors provides mechanical cues influencing tumor initiation and progression, its impact on ferroptosis and its mechanisms remains largely unexplored. In this study, we reveal that heightened mechanical tension sensitizes cells to ferroptosis, whereas decreased mechanics confers resistance. Mechanistically, reduced mechanical tension reduces intracellular free iron levels by enhancing FTH1 protein expression. Additionally, low mechanics significantly diminishes NCOA4, pivotal in mediating FTH1 phase separation-induced ferritinophagy. Targeting NCOA4 effectively rescues ferroptosis susceptibility under low mechanical tension through modulation of FTH1 phase separation-driven autophagy. In conclusion, our findings demonstrate that mechanics regulates iron metabolism via NCOA4-FTH1 phase separation-mediated autophagy, thereby influencing ferroptosis sensitivity and offering promising therapeutic avenues for future exploration.

{"title":"Autophagy induced by mechanical stress sensitizes cells to ferroptosis by the NCOA4-FTH1 axis.","authors":"Chenyu Luo, Haisheng Liang, Mintao Ji, Caiyong Ye, Yiping Lin, Yuhan Guo, Zhisen Zhang, Yinyin Shu, Xiaoni Jin, Shuangshuang Lu, Wanling Lu, Yazheng Dang, Hong Zhang, Bingyan Li, Guangming Zhou, Zengli Zhang, Lei Chang","doi":"10.1080/15548627.2025.2469129","DOIUrl":"https://doi.org/10.1080/15548627.2025.2469129","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent regulated form of cell death implicated in various diseases, including cancers, with its progression influenced by iron-dependent peroxidation of phospholipids and dysregulation of the redox system. Whereas the extracellular matrix of tumors provides mechanical cues influencing tumor initiation and progression, its impact on ferroptosis and its mechanisms remains largely unexplored. In this study, we reveal that heightened mechanical tension sensitizes cells to ferroptosis, whereas decreased mechanics confers resistance. Mechanistically, reduced mechanical tension reduces intracellular free iron levels by enhancing FTH1 protein expression. Additionally, low mechanics significantly diminishes NCOA4, pivotal in mediating FTH1 phase separation-induced ferritinophagy. Targeting NCOA4 effectively rescues ferroptosis susceptibility under low mechanical tension through modulation of FTH1 phase separation-driven autophagy. In conclusion, our findings demonstrate that mechanics regulates iron metabolism via NCOA4-FTH1 phase separation-mediated autophagy, thereby influencing ferroptosis sensitivity and offering promising therapeutic avenues for future exploration.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484983","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 Fe2+ influx through MCOLN1 channel prevents sustained inflammation by limiting PHDs-regulated NFKB activation in macrophages.
Pub Date : 2025-02-19 DOI: 10.1080/15548627.2025.2465396
Meng-Meng Wang, Wuyang Wang, Jiansong Qi

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.

{"title":"Lysosomal Fe<sup>2+</sup> 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":"<p><p>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 Fe<sup>2+</sup> 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 Fe<sup>2</sup> 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 <i>IL1B</i> 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 Fe<sup>2+</sup> through MCOLN1. Even more, by suppressing IL1B production, <i>in vivo</i> 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.</p>","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.
Pub Date : 2025-02-19 DOI: 10.1080/15548627.2025.2465395
Lei Feng, Xibao Li, Wenjin Shen, Caiji Gao

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.

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引用次数: 0
ESRRA (estrogen related receptor, alpha) induces ribosomal protein RPLP1-mediated adaptive hepatic translation during prolonged starvation.
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

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.

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引用次数: 0
Salmonella Typhimurium persistently infects host via its effector SseJ-induced PHB2-mediated mitophagy. 鼠伤寒沙门氏菌通过其效应物 SseJ 诱导的 PHB2 介导的有丝分裂持续感染宿主。
Pub Date : 2025-02-14 DOI: 10.1080/15548627.2025.2462511
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

Despite decades of research on effective methods to resist Salmonella enterica serovar Typhimurium (S. Typhimurium) pathogenicity, the mechanisms of S. Typhimurium-host interactions have not been fully determined. S. 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 S. Typhimurium replication and survival in the host. S. Typhimurium infection caused severe mitochondrial damage and mitophagy, which facilitated S. Typhimurium proliferation in cells. S. 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 S. Typhimurium. In conclusion, S. Typhimurium infection could be antagonized by targeting the SseJ-PHB2-mediated host mitochondrial autophagy pathway.Abbreviation: 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: Salmonella-containing vacuoles; siRNA: small interfering RNA; SPI-2: Salmonella pathogenicity island 2; SseJ: secretion system effector J; S. Typhimurium: Salmonella enterica serovar Typhimurium; S.T-ΔSseJ: SseJ gene-deleted Salmonella Typhimurium strains; S.T-CΔSseJ: SseJ-complemented Salmonella Typhimurium strains; WT: wild-type.

尽管数十年来人们一直在研究抵抗鼠伤寒沙门氏菌(S. Typhimurium)致病性的有效方法,但鼠伤寒沙门氏菌与宿主相互作用的机制尚未完全确定。鼠伤寒沙门氏菌因其地方流行性、高发病率和难以应用控制和预防措施等特点而成为全球公共卫生领域的重要人畜共患病。在此,我们介绍了一种新型细菌因子--分泌系统效应因子 J(SseJ)及其交互宿主蛋白 PHB2(禁止素 2)。我们探讨了 SseJ 是否会影响伤寒杆菌在宿主体内的复制和存活。鼠伤寒杆菌感染会造成严重的线粒体损伤和有丝分裂,从而促进鼠伤寒杆菌在细胞中的增殖。伤寒杆菌SseJ激活了PINK1(PTEN诱导激酶1)-PRKN(parkin RBR E3泛素蛋白连接酶)-依赖于自噬体的有丝分裂途径,在有丝分裂受体PHB2的帮助下,细菌得以存活并持续感染。此外,抑制有丝分裂可减轻伤寒杆菌的致病性。总之,可以通过靶向 SseJ-PHB2- 介导的宿主线粒体自噬途径来抑制伤寒杆菌感染。
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引用次数: 0
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