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Autophagy as a way to remove DNA lesions. 自噬是一种清除DNA损伤的方法。
Pub Date : 2025-03-01 Epub Date: 2024-12-15 DOI: 10.1080/15548627.2024.2434784
Yuchen Lei, Daniel J Klionsky

Type I topoisomerases (TOP1) are critical to remove the topological stress when DNA double strands are unwound. The TOP1 cleavage complexes (TOP1cc) are normally transient, and the stabilization of TOP1cc by its inhibitors, such as camptothecin (CPT), may lead to DNA damage and become cytotoxic. The proteasome pathway degrades trapped TOP1, which is necessary for the repair machinery to gain access to the DNA; however, this process is mainly described when the CPT concentration is high, at levels which are clinically unachievable. In a recently published study, Lascaux et al. identify macroautophagy/autophagy as a new pathway to remove DNA lesions upon clinically relevant low-dose CPT treatment. The autophagy receptor TEX264 binds to TOP1 and brings this protein and its bound DNA fragments to the phagophore; subsequently, they are ultimately delivered to the lysosome for degradation. This study demonstrates the role of autophagy in maintaining genome stability from a new perspective and reveals potential targets to deal with the resistance to TOP1cc inhibitors during cancer treatment.

I型拓扑异构酶(TOP1)是消除DNA双链解绕时拓扑应力的关键。TOP1切割复合物(TOP1cc)通常是短暂的,其抑制剂如喜树碱(CPT)对TOP1cc的稳定可能导致DNA损伤并具有细胞毒性。蛋白酶体途径降解捕获的TOP1,这是修复机制进入DNA所必需的;然而,这一过程主要发生在CPT浓度很高的情况下,达到临床无法达到的水平。在最近发表的一项研究中,Lascaux等人发现巨噬/自噬是通过临床相关的低剂量CPT治疗去除DNA病变的新途径。自噬受体TEX264与TOP1结合,并将该蛋白及其结合的DNA片段带到吞噬细胞;随后,它们最终被送到溶酶体降解。本研究从一个新的角度论证了自噬在维持基因组稳定性中的作用,并揭示了在癌症治疗过程中处理对TOP1cc抑制剂耐药的潜在靶点。
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引用次数: 0
HSP90 N-terminal inhibition promotes mitochondria-derived vesicles related metastasis by reducing TFEB transcription via decreased HSP90AA1-HCFC1 interaction in liver cancer. 在肝癌中,HSP90 N-端抑制通过减少HSP90AA1与HCFC1的相互作用,降低TFEB转录,从而促进线粒体衍生囊泡的相关转移。
Pub Date : 2025-03-01 Epub Date: 2024-11-11 DOI: 10.1080/15548627.2024.2421703
Lixia Liu, Zhenming Zheng, Yaling Huang, Hairou Su, Guibing Wu, Zihao Deng, Yan Li, Guantai Xie, Jieyou Li, Fei Zou, Xuemei Chen

Cancer cells compensate with increasing mitochondria-derived vesicles (MDVs) to maintain mitochondrial homeostasis, when canonical MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta)-mediated mitophagy is lacking. MDVs promote the transport of mitochondrial components into extracellular vesicles (EVs) and induce tumor metastasis. Although HSP90 (heat shock protein 90) chaperones hundreds of client proteins and its inhibitors suppress tumors, HSP90 inhibitors-related chemotherapy is associated with unexpected metastasis. Herein, we find that HSP90 inhibitor causes mitochondrial damage but stimulates the low LC3-induced MDVs and the release of MDVs-derived EVs. However, why LC3 decreases and what is the transcriptional regulatory mechanism of MDVs formation under HSP90 inhibition remain unknown. Because TFEB (transcription factor EB) is the most important mitophagy transcription factor, and the HSP90 client HCFC1 (host cell factor C1) regulates TFEB transcription, there should be a hidden connection between TFEB, HCFC1 and HSP90 in MDVs formation. Our results support the idea that HSP90 N-terminal inhibition reduces TFEB transcription via decreased HSP90AA1-HCFC1 interaction, which prevents HCFC1 from binding to the TFEB proximal promoter region. Decreased TFEB transcription and consequently reduced LC3, ultimately promoted MDVs formation. Blocking MDVs formation with the microtubule inhibitor nocodazole (NOC) activates the HCFC1-TFEB-LC3 axis, weakens HSP90 inhibitors-induced MDVs and the release of MDVs-derived EVs, inhibits the growth of tumor cell spheres and primary liver tumors, and reduces the extravasation of cancer cells to secondary metastatic sites. Taken together, these data suggest that combination therapy should be used to reduce the metastatic risk of low TFEB-triggered-MDVs formation caused by HSP90 inhibitors.Abbreviation: ACIs: ATP-competitive inhibitors; BaFA1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CTD: C-terminal domain; EVs: extracellular vesicles; HCFC1: host cell factor C1; HSP90: heat shock protein 90; ILVs: intralumenal vesicles; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MD: middle domain; MDVs: mitochondria-derived vesicles; MQC: mitochondrial quality control; ΔΨm: mitochondrial membrane potential; MVBs: multivesicular bodies; NB: novobiocin; TEM: transmission electron microscopy; TFEB: transcription factor EB; TFs: transcription factors. NOC: nocodazole; NTD: N-terminal nucleotide binding domain; OCR: oxygen consumption rate; RFP: red fluorescent protein; ROS: reactive oxygen species; STA9090: Ganetespib; VPS35: VPS35 retromer complex component.

当缺乏典型的 MAP1LC3B/LC3B(微管相关蛋白 1 轻链 3 beta)介导的有丝分裂时,癌细胞会通过增加线粒体衍生囊泡(MDVs)来维持线粒体的平衡。MDV 促进线粒体成分向细胞外囊泡 (EV) 的运输,并诱发肿瘤转移。虽然 HSP90(热休克蛋白 90)能合成数百种客户蛋白,其抑制剂也能抑制肿瘤,但与 HSP90 抑制剂相关的化疗却会导致意想不到的转移。在这里,我们发现 HSP90 抑制剂会导致线粒体损伤,但会刺激低 LC3 诱导的 MDVs 和 MDVs 衍生 EVs 的释放。然而,在 HSP90 抑制作用下,LC3 为什么会减少,MDVs 形成的转录调控机制是什么,这些仍然是未知数。由于TFEB(转录因子EB)是最重要的有丝分裂吞噬转录因子,而HSP90的客户HCFC1(宿主细胞因子C1)调控TFEB的转录,因此在MDVs形成过程中,TFEB、HCFC1和HSP90之间应该存在隐性联系。我们的研究结果支持这样一种观点,即 HSP90 N 端抑制通过减少 HSP90AA1 与 HCFC1 的相互作用来减少 TFEB 的转录,从而阻止 HCFC1 与 TFEB 近端启动子区域结合。TFEB 转录的减少以及 LC3 的减少最终促进了 MDVs 的形成。用微管抑制剂nocodazole(NOC)阻断MDVs的形成可激活HCFC1-TFEB-LC3轴,削弱HSP90抑制剂诱导的MDVs和MDVs衍生EVs的释放,抑制肿瘤细胞球和原发性肝肿瘤的生长,并减少癌细胞向继发性转移部位的外渗。综上所述,这些数据表明,应采用联合疗法来降低 HSP90 抑制剂导致的低 TFEB 触发 MDVs 形成的转移风险。
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引用次数: 0
Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through ATP6V0D2-mediated autophagic degradation of EPAS1/HIF2α. 白术内酯I通过ATP6V0D2介导的EPAS1/HIF2α自噬降解抑制血管生成并逆转透明细胞肾细胞癌的舒尼替尼耐药性。
Pub Date : 2025-03-01 Epub Date: 2024-11-04 DOI: 10.1080/15548627.2024.2421699
Qinyu Li, Kai Zeng, Qian Chen, Chenglin Han, Xi Wang, Beining Li, Jianping Miao, Bolong Zheng, Jihong Liu, Xianglin Yuan, Bo Liu

Clear cell renal cell carcinoma (ccRCC) is tightly associated with VHL (von Hippel-Lindau tumor suppressor) mutation and dysregulated angiogenesis. Accumulating evidence indicates that antiangiogenic treatment abolishing tumor angiogenesis can achieve longer disease-free survival in patients with ccRCC. Atractylenolide I (ATL-I) is one of the main active compounds in Atractylodes macrocephala root extract and exhibits various pharmacological effects, including anti-inflammatory and antitumor effects. In this study, we revealed the potent antitumor activity of ATL-I in ccRCC. ATL-I exhibited robust antiangiogenic capacity by inhibiting EPAS1/HIF2α-mediated VEGFA production in VHL-deficient ccRCC, and it promoted autophagic degradation of EPAS1 by upregulating the ATPase subunit ATP6V0D2 (ATPase H+ transporting V0 subunit d2) to increase lysosomal function and facilitated fusion between autophagosomes and lysosomes. Mechanistically, ATP6V0D2 directly bound to RAB7 and VPS41 and promoted the RAB7-HOPS interaction, facilitating SNARE complex assembly and autophagosome-lysosome fusion. Moreover, ATP6V0D2 promoted autolysosome degradation by increasing the acidification and activity of lysosomes during the later stages of macroautophagy/autophagy. Additionally, we found that ATL-I could decrease the level of EPAS1, which was upregulated in sunitinib-resistant cells, thus reversing sunitinib resistance. Collectively, our findings demonstrate that ATL-I is a robust antiangiogenic and antitumor lead compound with potential clinical application for ccRCC therapy.Abbreviations: ATL-I: atractylenolide I; ATP6V0D2: ATPase H+ transporting V0 subunit d2; CAM: chick chorioallantoic membrane; ccRCC: clear cell renal cell carcinoma; CTSB: cathepsin B; CTSD: cathepsin D; GO: Gene Ontology; HIF-1: HIF1A-ARNT heterodimer; HOPS: homotypic fusion and protein sorting; KDR/VEGFR: kinase insert domain receptor; KEGG: Kyoto Encyclopedia of Genes and Genomes; RCC: renal cell carcinoma; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TKI: tyrosine kinase inhibitor; V-ATPase: vacuolar-type H±translocating ATPase; VEGF: vascular endothelial growth factor; VHL: von Hippel-Lindau tumor suppressor.

透明细胞肾细胞癌(ccRCC)与VHL(von Hippel-Lindau肿瘤抑制因子)突变和血管生成失调密切相关。越来越多的证据表明,消除肿瘤血管生成的抗血管生成治疗可以延长ccRCC患者的无病生存期。白术内酯 I(ATL-I)是白术根提取物中的主要活性化合物之一,具有多种药理作用,包括抗炎和抗肿瘤作用。本研究揭示了 ATL-I 在 ccRCC 中的强效抗肿瘤活性。ATL-I通过抑制EPAS1/HIF2α介导的VEGFA生成,在VHL缺陷的ccRCC中表现出强大的抗血管生成能力,并通过上调ATP酶亚基ATP6V0D2(ATP酶H+转运V0亚基d2)促进EPAS1的自噬降解,从而增强溶酶体功能,促进自噬体和溶酶体之间的融合。从机制上讲,ATP6V0D2直接与RAB7和VPS41结合,促进了RAB7-HOPS的相互作用,有利于SNARE复合物的组装和自噬体与溶酶体的融合。此外,在大自噬/自噬的后期阶段,ATP6V0D2通过提高溶酶体的酸化和活性促进自溶酶体降解。此外,我们还发现 ATL-I 能降低舒尼替尼耐药细胞中上调的 EPAS1 水平,从而逆转舒尼替尼耐药。总之,我们的研究结果表明,ATL-I 是一种强效的抗血管生成和抗肿瘤先导化合物,具有临床应用于 ccRCC 治疗的潜力。
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引用次数: 0
Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion.
Pub Date : 2025-02-27 DOI: 10.1080/15548627.2025.2472586
Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Gary Shangguan, Joseph M Wider, Maik Hüttemann, Thomas H Sanderson

Mitochondrial damage and dysfunction are hallmarks of neuronal injury during cerebral ischemia-reperfusion (I/R). Critical mitochondrial functions including energy production and cell signaling are perturbed during I/R, often exacerbating damage and contributing to secondary injury. The integrity of the mitochondrial proteome is essential for efficient function. Mitochondrial proteostasis is mediated by the cooperative forces of mitophagy and intramitochondrial proteolysis. The aim of this study was to elucidate the patterns of mitochondrial protein dynamics and their key regulators during an in vitro model of neuronal I/R injury. Utilizing the MitoTimer reporter, we quantified mitochondrial protein oxidation and turnover during I/R injury, highlighting a key point at 2 h reoxygenation for aged/oxidized protein turnover. This turnover was found to be mediated by both LONP1-dependent proteolysis and PRKN/parkin-dependent mitophagy. Additionally, the proteostatic response of neuronal mitochondria is influenced by both mitochondrial fusion and fission machinery. Our findings highlight the involvement of both mitophagy and intramitochondrial proteolysis in the response to I/R injury.

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引用次数: 0
A bacterial RING ubiquitin ligase triggering stepwise degradation of BRISC via TOLLIP-mediated selective autophagy manipulates host inflammatory response. 细菌 RING 泛素连接酶通过 TOLLIP 介导的选择性自噬触发 BRISC 的逐步降解,从而操纵宿主的炎症反应。
Pub Date : 2025-02-27 DOI: 10.1080/15548627.2025.2468140
Xinming Pan, Yangyang Sun, Jianan Liu, Rong Chen, Zhen Zhang, Caiying Li, Huochun Yao, Jiale Ma

Numerous bacterial pathogens have evolved tactics to interfere with the host ubiquitination network to evade clearance by the innate immune system. Nevertheless, the subtle antagonism between a bacterial ubiquitinase and a host deubiquitinase, through which they modify their respective targets within a multifaceted network, has yet to be characterized. BRCC3 isopeptidase complex (BRISC) is a newly identified K63-specific deubiquitinase complex that plays a crucial role in cellular signaling pathways such as inflammation. NleG, a type III secretion system (T3SS) effector, contains a conserved RING E3 ubiquitin ligase domain that interacts with host ubiquitination machinery, along with a distinct substrate-recognition domain that targets host proteins. Here, one particular variant, NleG6, was identified as mediating K27- and K29-linked polyubiquitination at residues K89 and K114 of ABRAXAS2/FAM175B, a scaffolding protein within the BRISC complex, leading to its degradation through TOLLIP (toll interacting protein)-mediated selective autophagy. Further investigations elucidated that ABRAXAS2 degradation triggered the subsequent degradation of adjacent BRCC3, which in turn, hindered TNIP1/ABIN1 degradation, ultimately inhibiting NFKB/NF-κB (nuclear factor kappa B)-mediated inflammatory responses. This chain of events offers valuable insights into the NFKB activation by the K63-specific deubiquitinating role of BRISC, unveiling how bacteria manipulate ubiquitin regulation and selective autophagy within the BRISC network to inhibit the host's inflammatory response and thus dominate a pathogen-host tug-of-war.Abbreviations: 3-MA: 3-methyladenine; A/E: attaching and effacing; ATG7: autophagy related 7; BafA1: bafilomycin A1; BNIP3L/Nix: BCL2 interacting protein 3 like; BRISC: BRCC3 isopeptidase complex; Cas9: CRISPR-associated system 9; co-IP: co-immunoprecipitation; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; DAPI: 4',6-diamidino2-phenylindole; DMSO: dimethyl sulfoxide; DUB: deubiquitinating enzyme; E. coli: Escherichia coli; EHEC: enterohemorrhagic Escherichia coli; EPEC: enteropathogenic Escherichia coli; GFP: green fluorescent protein; LEE: locus of enterocyte effacement; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MG132: cbz-leu-leu-leucinal; MOI: multiplicity of infection; NBR1: NBR1 autophagy cargo receptor; NC: negative control; NFKB/NF-κB: nuclear factor kappa B; NH4Cl: ammonium chloride; OPTN: optineurin; SQSTM1/p62: sequestosome 1; sgRNAs: small guide RNAs; T3SS: type III secretion system; TNF: tumor necrosis factor; TOLLIP: toll interacting protein; TRAF: TNF receptor associated factor; TUBB: tubulin beta class I; WCL: whole cell lysate; WT: wide type.

{"title":"A bacterial RING ubiquitin ligase triggering stepwise degradation of BRISC via TOLLIP-mediated selective autophagy manipulates host inflammatory response.","authors":"Xinming Pan, Yangyang Sun, Jianan Liu, Rong Chen, Zhen Zhang, Caiying Li, Huochun Yao, Jiale Ma","doi":"10.1080/15548627.2025.2468140","DOIUrl":"https://doi.org/10.1080/15548627.2025.2468140","url":null,"abstract":"<p><p>Numerous bacterial pathogens have evolved tactics to interfere with the host ubiquitination network to evade clearance by the innate immune system. Nevertheless, the subtle antagonism between a bacterial ubiquitinase and a host deubiquitinase, through which they modify their respective targets within a multifaceted network, has yet to be characterized. BRCC3 isopeptidase complex (BRISC) is a newly identified K63-specific deubiquitinase complex that plays a crucial role in cellular signaling pathways such as inflammation. NleG, a type III secretion system (T3SS) effector, contains a conserved RING E3 ubiquitin ligase domain that interacts with host ubiquitination machinery, along with a distinct substrate-recognition domain that targets host proteins. Here, one particular variant, NleG6, was identified as mediating K27- and K29-linked polyubiquitination at residues K89 and K114 of ABRAXAS2/FAM175B, a scaffolding protein within the BRISC complex, leading to its degradation through TOLLIP (toll interacting protein)-mediated selective autophagy. Further investigations elucidated that ABRAXAS2 degradation triggered the subsequent degradation of adjacent BRCC3, which in turn, hindered TNIP1/ABIN1 degradation, ultimately inhibiting NFKB/NF-κB (nuclear factor kappa B)-mediated inflammatory responses. This chain of events offers valuable insights into the NFKB activation by the K63-specific deubiquitinating role of BRISC, unveiling how bacteria manipulate ubiquitin regulation and selective autophagy within the BRISC network to inhibit the host's inflammatory response and thus dominate a pathogen-host tug-of-war.<b>Abbreviations:</b> 3-MA: 3-methyladenine; A/E: attaching and effacing; ATG7: autophagy related 7; BafA1: bafilomycin A<sub>1</sub>; BNIP3L/Nix: BCL2 interacting protein 3 like; BRISC: BRCC3 isopeptidase complex; Cas9: CRISPR-associated system 9; co-IP: co-immunoprecipitation; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; DAPI: 4',6-diamidino2-phenylindole; DMSO: dimethyl sulfoxide; DUB: deubiquitinating enzyme; <i>E. coli</i>: <i>Escherichia coli</i>; EHEC: enterohemorrhagic <i>Escherichia coli</i>; EPEC: enteropathogenic <i>Escherichia coli</i>; GFP: green fluorescent protein; LEE: locus of enterocyte effacement; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MG132: cbz-leu-leu-leucinal; MOI: multiplicity of infection; NBR1: NBR1 autophagy cargo receptor; NC: negative control; NFKB/NF-κB: nuclear factor kappa B; NH<sub>4</sub>Cl: ammonium chloride; OPTN: optineurin; SQSTM1/p62: sequestosome 1; sgRNAs: small guide RNAs; T3SS: type III secretion system; TNF: tumor necrosis factor; TOLLIP: toll interacting protein; TRAF: TNF receptor associated factor; TUBB: tubulin beta class I; WCL: whole cell lysate; WT: wide type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517670","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
Heat-shock chaperone HSPB1 mitigates poly-glycine-induced neurodegeneration via restoration of autophagic flux.
Pub Date : 2025-02-25 DOI: 10.1080/15548627.2025.2466144
Ning Ding, Yijie Song, Yuhang Zhang, Wei Yu, Xinnan Li, Wei Li, Lei Li

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 GIPC1 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.Abbreviations: 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.

{"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 A<sub>1</sub>: bafilomycin A<sub>1</sub>; 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":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","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}
引用次数: 0
Correction.
Pub Date : 2025-02-25 DOI: 10.1080/15548627.2025.2450891
{"title":"Correction.","authors":"","doi":"10.1080/15548627.2025.2450891","DOIUrl":"https://doi.org/10.1080/15548627.2025.2450891","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495023","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
Calcium release from damaged lysosomes triggers stress granule formation for cell survival.
Pub Date : 2025-02-24 DOI: 10.1080/15548627.2025.2468910
Aravinth Kumar Jayabalan, Aanuoluwakiitan Ayeni, Jingyue Jia

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.

{"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<sup>ORF3a</sup>, 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":"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.
Pub Date : 2025-02-24 DOI: 10.1080/15548627.2025.2469206
Danielle Henn, Xi Yang, Ming Li

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.

{"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":"<p><p>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.<b>Abbreviation</b>: 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)P<sub>2</sub>: phosphatidylinositol-4,5-bisphosphate; V-ATPase: vacuolar-type H<sup>+</sup>-translocating ATPase.</p>","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.
Pub Date : 2025-02-24 DOI: 10.1080/15548627.2025.2465408
Tomokazu Murakawa, Kinya Otsu

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.

{"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":"<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<sup>S272A</sup> 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":"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
期刊
Autophagy
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