Biochimica et Biophysica Acta-Gene Regulatory Mechanisms最新文献

{"title":"The versatility of the proteasome in gene expression and silencing: Unraveling proteolytic and non-proteolytic functions","authors":"Hyesu Lee ,&nbsp;Sungwook Kim ,&nbsp;Daeyoup Lee","doi":"10.1016/j.bbagrm.2023.194978","DOIUrl":"10.1016/j.bbagrm.2023.194978","url":null,"abstract":"<div><p><span>The 26S proteasome consists of a 20S core particle and a 19S regulatory particle and critically regulates gene expression and silencing through both proteolytic and non-proteolytic functions. The 20S core particle mediates </span>proteolysis<span><span>, while the 19S regulatory particle performs non-proteolytic functions. The proteasome plays a role in regulating gene expression in euchromatin<span> by modifying histones, activating transcription, initiating and terminating transcription, mRNA export, and maintaining </span></span>transcriptome<span><span> integrity. In gene silencing, the proteasome modulates the heterochromatin formation, spreading, and </span>subtelomere silencing by degrading specific proteins and interacting with anti-silencing factors such as Epe1, Mst2, and Leo1. This review discusses the proteolytic and non-proteolytic functions of the proteasome in regulating gene expression and gene silencing-related heterochromatin formation. This article is part of a special issue on the regulation of gene expression and genome integrity by the ubiquitin-proteasome system.</span></span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194978"},"PeriodicalIF":4.7,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10118733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitination and deubiquitination: Implications on cancer therapy","authors":"Gunjan Dagar ,&nbsp;Rakesh Kumar ,&nbsp;Kamlesh K. Yadav ,&nbsp;Mayank Singh ,&nbsp;Tej K. Pandita","doi":"10.1016/j.bbagrm.2023.194979","DOIUrl":"10.1016/j.bbagrm.2023.194979","url":null,"abstract":"<div><p>The ubiquitin proteasomal system (UPS) represents a highly regulated protein degradation<span><span><span> pathway essential for maintaining cellular homeostasis. This system plays a critical role in several cellular processes, which include DNA damage repair, </span>cell cycle checkpoint control, and immune response regulation. Recently, the UPS has emerged as a promising target for cancer therapeutics due to its involvement in oncogenesis and tumor progression. Here we aim to summarize the key aspects of the UPS and its significance in cancer therapeutics. We begin by elucidating the fundamental components of the UPS, highlighting the role of ubiquitin, E1-E3 </span>ligases<span><span>, and the proteasome<span> in protein degradation. Furthermore, we discuss the intricate process of ubiquitination and proteasomal degradation, emphasizing the specificity and selectivity achieved through various </span></span>signaling pathways<span><span>. The dysregulation of the UPS has been implicated in cancer development and progression. Aberrant ubiquitin-mediated degradation of key regulatory proteins, such as tumor suppressors and oncoproteins, can lead to uncontrolled </span>cell proliferation<span><span>, evasion of apoptosis, and metastasis. We outline the pivotal role of the UPS in modulating crucial oncogenic pathways, including the regulation of cyclins, transcription factors, Replication stress components and DNA damage response. The increasing recognition of the UPS as a target for cancer therapeutics has spurred the development of </span>small molecules<span>, peptides, and proteasome inhibitors<span> with the potential to restore cellular balance and disrupt tumor growth. We provide an overview of current therapeutic strategies aimed at exploiting the UPS, including the use of proteasome inhibitors, deubiquitinating enzyme inhibitors, and novel E3 ligase modulators. We further discuss novel emerging strategies for the development of next-generation drugs that target proteasome inhibitors. Exploiting the UPS for cancer therapeutics offers promising avenues for developing innovative and effective treatment strategies, providing hope for improved patient outcomes in the fight against cancer.</span></span></span></span></span></span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194979"},"PeriodicalIF":4.7,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10142364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein post-translational modifications: A key factor in colorectal cancer resistance mechanisms","authors":"Bo Bi ,&nbsp;Miaojuan Qiu ,&nbsp;Peng Liu ,&nbsp;Qiang Wang ,&nbsp;Yingfei Wen ,&nbsp;You Li ,&nbsp;Binbin Li ,&nbsp;Yongshu Li ,&nbsp;Yulong He ,&nbsp;Jing Zhao","doi":"10.1016/j.bbagrm.2023.194977","DOIUrl":"10.1016/j.bbagrm.2023.194977","url":null,"abstract":"<div><p>Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Despite advances in treatment, drug resistance remains a critical impediment. Post-translational modifications (PTMs) regulate protein stability, localization, and activity, impacting vital cellular processes. Recent research has highlighted the essential role of PTMs in the development of CRC resistance. This review summarizes recent advancements in understanding PTMs' roles in CRC resistance, focusing on the latest discoveries. We discuss the functional impact of PTMs on signaling pathways and molecules involved in CRC resistance, progress in drug development, and potential therapeutic targets. We also summarize the primary enrichment methods for PTMs. Finally, we discuss current challenges and future directions, including the need for more comprehensive PTM analysis methods and PTM-targeted therapies. This review identifies potential therapeutic interventions for addressing medication resistance in CRC, proposes prospective therapeutic options, and gives an overview of the function of PTMs in CRC resistance.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194977"},"PeriodicalIF":4.7,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10494009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-translational modifications of lysine-specific demethylase 1","authors":"Dongha Kim ,&nbsp;Hye Jin Nam ,&nbsp;Sung Hee Baek","doi":"10.1016/j.bbagrm.2023.194968","DOIUrl":"10.1016/j.bbagrm.2023.194968","url":null,"abstract":"<div><p>Lysine-specific demethylase 1 (LSD1) is crucial for regulating gene expression by catalyzing the demethylation of mono- and di-methylated histone H3 lysine 4 (H3K4) and lysine 9 (H3K9) and non-histone proteins through the amine oxidase activity with FAD⁺ as a cofactor. It interacts with several protein partners, which potentially contributes to its diverse substrate specificity. Given its pivotal role in numerous physiological and pathological conditions, the function of LSD1 is closely regulated by diverse post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, and acetylation. In this review, we aim to provide a comprehensive understanding of the regulation and function of LSD1 following various PTMs. Specifically, we will focus on the impact of PTMs on LSD1 function in physiological and pathological contexts and discuss the potential therapeutic implications of targeting these modifications for the treatment of human diseases.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194968"},"PeriodicalIF":4.7,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10082073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N6-methyladenosine (m6A) methylation in kidney diseases: Mechanisms and therapeutic potential","authors":"Yuting Sun ,&nbsp;De Jin ,&nbsp;Ziwei Zhang ,&nbsp;Hangyu Ji ,&nbsp;Xuedong An ,&nbsp;Yuehong Zhang ,&nbsp;Cunqing Yang ,&nbsp;Wenjie Sun ,&nbsp;Yuqing Zhang ,&nbsp;Yingying Duan ,&nbsp;Xiaomin Kang ,&nbsp;Linlin Jiang ,&nbsp;Xuefei Zhao ,&nbsp;Fengmei Lian","doi":"10.1016/j.bbagrm.2023.194967","DOIUrl":"10.1016/j.bbagrm.2023.194967","url":null,"abstract":"<div><p>The N6-methyladenosine (m6A) modification is regulated by methylases, commonly referred to as “writers,” and demethylases, known as “erasers,” leading to a dynamic and reversible process. Changes in m6A levels have been implicated in a wide range of cellular processes, including nuclear RNA export, mRNA metabolism, protein translation, and RNA splicing, establishing a strong correlation with various diseases. Both physiologically and pathologically, m6A methylation plays a critical role in the initiation and progression of kidney disease. The methylation of m6A may also facilitate the early diagnosis and treatment of kidney diseases, according to accumulating research. This review aims to provide a comprehensive overview of the potential role and mechanism of m6A methylation in kidney diseases, as well as its potential application in the treatment of such diseases. There will be a thorough examination of m6A methylation mechanisms, paying particular attention to the interplay between m6A writers, m6A erasers, and m6A readers. Furthermore, this paper will elucidate the interplay between various kidney diseases and m6A methylation, summarize the expression patterns of m6A in pathological kidney tissues, and discuss the potential therapeutic benefits of targeting m6A in the context of kidney diseases.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194967"},"PeriodicalIF":4.7,"publicationDate":"2023-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9993758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ETS2 overexpression ameliorates cartilage injury in osteoarthritis by the ETS2/miR-155/STAT1/DNMT1 feedback loop pathway","authors":"Shuxiang Chen ,&nbsp;Xiaotong Zhu ,&nbsp;Wenhuan Ou ,&nbsp;Le Kang ,&nbsp;Jian Situ ,&nbsp;Zhipeng Liao ,&nbsp;Li Huang ,&nbsp;Weizhong Qi ,&nbsp;Songjia Ni","doi":"10.1016/j.bbagrm.2023.194965","DOIUrl":"10.1016/j.bbagrm.2023.194965","url":null,"abstract":"<div><p><span><span><span>Osteoarthritis (OA) is the most common irreversible chronic joint dysfunction disease, which is pathologically characterized by disturbance of articular cartilage homeostasis leading to subsequent inflammatory response and cartilage extracellular matrix (ECM) degradation. Increasing evidence has demonstrated the dysregulation of transcription factors play crucial roles in the occurrence and development of osteoarthritis (OA), but the potential functions and mechanism of most transcription factors in OA has not been completely illuminated. In this study, we identified that transcription factor V-ets erythroblastosis virus E26 </span>oncogene homolog 2 (ETS2) was significantly down-regulated in OA cartilage and IL-1β-induced OA </span>chondrocytes<span>. Functional experiments in vitro demonstrated that the overexpressed ETS2 strikingly enhanced proliferation, outstandingly suppressed apoptosis, and dramatically reduced inflammation and ECM degradation in IL-1β-induced OA chondrocytes, whereas the knockdown of ETS2 led to the opposite effects. Further in vivo studies<span> have shown that up-regulated ETS2 dramatically ameliorates cartilage injury in DMM-induced OA mice. Mechanical studies have disclosed that DNMT1-mediated downregulation of ETS2 dramatically promotes STAT1 by inhibiting miR-155 transcription, and increased STAT1 initiates a feedback loop that may enhance DNMT1-mediated hypermethylation of ETS2 to inhibit ETS2 expression, thus forming a DNMT1/ETS2/miR-155/STAT1 feedback loop that inhibits MAPK </span></span></span>signaling pathways and aggravates OA cartilage injury. In all, our results revealed that overexpression of ETS2 markedly ameliorated OA cartilage injury through the ETS2/miR-155/STAT1/DNMT1 feedback loop, providing a new perspective on the pathogenesis and therapeutic strategies for OA.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194965"},"PeriodicalIF":4.7,"publicationDate":"2023-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10386661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence","authors":"Tamara Rosell-Garcia ,&nbsp;Sergio Rivas-Muñoz ,&nbsp;Koryu Kin ,&nbsp;Verónica Romero-Albillo ,&nbsp;Silvia Alcaraz ,&nbsp;Carlos Fernandez-Tornero ,&nbsp;Fernando Rodriguez-Pascual","doi":"10.1016/j.bbagrm.2023.194963","DOIUrl":"10.1016/j.bbagrm.2023.194963","url":null,"abstract":"<div><p>Transcriptional activity of the hypoxia inducible factor (HIF) relies on the formation of a heterodimer composed of an oxygen-regulated α-subunit and a stably expressed β-subunit. Heterodimeric HIF activates expression by binding to RCGTG motifs within promoters of hypoxia-activated genes. Some hypoxia targets also possess an adjacent HIF ancillary sequence (HAS) reported to increase transcription but whose function remains obscure. Here, we investigate the contribution of the HAS element to the hypoxia response and its mechanism of action, using the HAS-containing prolyl 4-hydroxylase subunit α1 (P4HA1) as a gene model in NIH/3T3 mouse embryonic fibroblasts and HEK293 human embryonic kidney cells. Our HIF overexpression experiments demonstrate that the HAS motif is essential for full induction by hypoxia and that the presence of the tandem HAS/HIF, as opposed to HIF-only sequences, provides HIF proteins with the capacity to form complexes of stoichiometry beyond the classical heterodimer, likely tetramers, to cooperatively potentiate hypoxia-induced transcription. We also provide evidence of the crucial role played by the Fα helix of the PAS-B domain of the HIF1β subunit to support the interaction between heterodimers. Functional analysis showed that human genes containing the HAS/HIF motifs are better responders to hypoxia, and their promoters are enriched for specific transcription factor binding sites. Gene ontology enrichment revealed a predominance of HAS/HIF in genes primarily related to tissue formation and development. Our findings add an extra level of regulation of the hypoxia/HIF signaling through multimerization of HIF proteins on regulatory elements containing the HAS/HIF motifs.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194963"},"PeriodicalIF":4.7,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10135904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Damaged collagen detected by collagen hybridizing peptide as efficient diagnosis marker for early hepatic fibrosis","authors":"Ping Tao ,&nbsp;Jinfang Liu ,&nbsp;Yuan Li ,&nbsp;Tao Zhang ,&nbsp;Fangzhou Wang ,&nbsp;Lei Chang ,&nbsp;Chonghui Li ,&nbsp;Xinlan Ge ,&nbsp;Tao Zuo ,&nbsp;Shichun Lu ,&nbsp;Yuanyuan Ruan ,&nbsp;Zhimin Yang ,&nbsp;Ping Xu","doi":"10.1016/j.bbagrm.2023.194928","DOIUrl":"10.1016/j.bbagrm.2023.194928","url":null,"abstract":"<div><p>Liver fibrosis is characterized by excessive synthesis and deposition of extracellular matrix (ECM) in liver tissues. However, it still has been lacking of early detection and diagnosis methods. The collagen hybridizing peptide (CHP) is a novel synthetic peptide that enables detection of collagen damage and tissue remodeling. Here, we showed that obvious CHP-positive staining could be detected in the liver while given CCl₄ for only 3 days, which was significantly enhanced while given CCl₄ for 7 days. However, H&amp;E staining showed no significant changes in fibrous tissue, and sirius red-positive staining could only be observed while given CCl₄<span> for 14 days. Moreover, CHP-positive staining enhanced initially at portal area which further extended into the hepatic lobule, which was increased more significantly than sirius red-positive staining in the model of 10 and 14 days. Further proteomic<span><span><span> analysis of CHP-positive staining revealed that pathways associated with ECM remodeling were significantly increased, while retinol metabolism was downregulated. Meanwhile, proteins enriched in cellular </span>gene transcription and </span>signal transduction<span> involved in fibrogenesis were also upregulated, suggesting that fibrosis occurred in CHP-positive staining. Our study provided evidence that CHP could detect the collagen damage in liver, which might be an efficient indicator for the diagnosis of liver fibrosis at a very early stage.</span></span></span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 2","pages":"Article 194928"},"PeriodicalIF":4.7,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9536210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3 activates PERK-eIF2α dependent coelomocyte apoptosis by targeting the endoplasmic reticulum degradation-related protein SEL1L in echinoderms","authors":"Dongdong Li ,&nbsp;Ming Guo ,&nbsp;Zhimeng Lv ,&nbsp;Yina Shao ,&nbsp;Weikang Liang ,&nbsp;Chenghua Li","doi":"10.1016/j.bbagrm.2023.194927","DOIUrl":"10.1016/j.bbagrm.2023.194927","url":null,"abstract":"<div><p><span>N6-methyladenosine (m6A) plays an important role in regulating many physiological and disease processes in vertebrates, in which methyltransferase-like 3 (METTL3) is the best-known m6A methyltransferase. However, the functional roles of invertebrate METTL3 have not yet been highlighted. In this study, we found that METTL3 from </span><span><em>Apostichopus japonicus</em></span> (AjMETTL3) was significantly induced in coelomocytes accompanied by higher levels of m6A modification in response to <span><em>Vibrio splendidus</em></span> challenge. Overexpression or silencing of <em>AjMETTL3</em> in coelomocytes increased or decreased the m6A levels and promoted or inhibited <em>V. splendidus</em><span>-induced coelomocyte apoptosis, respectively. To further explore the molecular mechanism of AjMETTL3-mediated coelomic immunity, m6A-seq analysis revealed that the endoplasmic reticulum-related degradation (ERAD) pathway was significantly enriched, in which suppressor/enhancer of Lin-12-like (</span><em>AjSEL1L)</em> was suggested to be a target of AjMETTL3 in a negative regulatory manner. Functional analysis revealed that the increased AjMETTL3 reduced the stability of <em>AjSEL1L</em> mRNA by targeting the m6A modification site of 2004 bp-GGACA-2008 bp. The decreased AjSEL1L was further confirmed to be involved in AjMETTL3-mediated coelomocyte apoptosis. Mechanistically, the inhibited <em>AjSEL1L</em><span> increased the transcription of AjOS9 and Ajp97 in the EARD pathway to promote ubiquitin protein accumulation and ER stress, which further activated AjPERK-AjeIF2α pathway dependent coelomocyte apoptosis, but not the AjIRE1 or AjATF6 pathway. Taken together, our results supported invertebrate METTL3-mediated coelomocyte apoptosis by regulating the PERK-eIF2α pathway.</span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 2","pages":"Article 194927"},"PeriodicalIF":4.7,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9543957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formation of aggresomes with hydrogel-like characteristics by proteasome inhibition","authors":"Seo Hyeong Park ,&nbsp;Sang-Eun Lee ,&nbsp;Jun Hyoung Jeon ,&nbsp;Jung Hoon Lee ,&nbsp;Eisuke Itakura ,&nbsp;Sunghoe Chang ,&nbsp;Won Hoon Choi ,&nbsp;Min Jae Lee","doi":"10.1016/j.bbagrm.2023.194932","DOIUrl":"10.1016/j.bbagrm.2023.194932","url":null,"abstract":"<div><p><span><span>The spatiotemporal sequestration of misfolded proteins is a mechanism by which cells counterbalance proteome </span>homeostasis<span> upon exposure to various stress stimuli. Chronic inhibition of proteasomes results in a large, juxtanuclear, membrane-less inclusion, known as the </span></span>aggresome<span>. Although the molecular mechanisms driving its formation, clearance, and pathophysiological implications are continuously being uncovered, the biophysical aspects of aggresomes remain largely uncharacterized. Using fluorescence recovery after photobleaching and liquid droplet disruption assays, we found that the aggresomes are a homogeneously blended condensates with liquid-like properties similar to droplets formed via liquid–liquid phase separation. However, unlike fluidic liquid droplets, aggresomes have more viscosity and hydrogel-like characteristics. We also observed that the inhibition of aggresome formation using microtubule-disrupting agents resulted in less soluble and smaller cytoplasmic speckles, which was associated with marked cytotoxicity. Therefore, the aggresome appears to be cytoprotective and serves as a temporal reservoir for dysfunctional proteasomes and substrates that need to be degraded. Our results suggest that the aggresome assembles through distinct and potentially sequential processes of energy-dependent retrograde transportation and spontaneous condensation into a hydrogel.</span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 2","pages":"Article 194932"},"PeriodicalIF":4.7,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9914451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}