{"title":"NF-кB promotes aggresome formation via upregulating HDAC6 and in turn maintaining Vimentin cage.","authors":"Jo-Mei Maureen Chen, Cheng-Yen Chuang, Chiao-Yun Cheng, Yu-Ting Amber Liao, Yi-Hao Calvin Liao, Chih-Ming Pan, Yu-Ting Jenny Huang, Tong-You Wade Wei, Jia-Rong Tsai, Li-Wen Lee, Shao-Chih Chiu, Chang-Tze Ricky Yu","doi":"10.1152/ajpcell.00671.2023","DOIUrl":null,"url":null,"abstract":"<p><p>Proteasome inhibitors have been applied to anticancer therapy by accumulating toxic misfolded proteins. However, chemical inactivation of proteasome generates aggresome, a Vimentin cage-enclosed subcellular structure quarantining HDAC6-Dynein-transported misfolded proteins before the protein toxicants are degraded by autophagy. Hence, aggresome may attenuate proteasome inhibitor drug-induced cytotoxicity. To solve the problem, it is imperative to characterize how cells assemble aggresome. By examining aggresomes in six cell lines, A549 cells were selectively studied for their bigger cell size and moderate aggresome-forming activity. Aggresome grew in size upon continuous exposure of A549 cells to proteasome inhibitor MG132 and reached a mature size around the 16th to 24th hour of treatment. Mechanistic studies revealed that NF-кB translocated to the nucleus in MG132-treated cells, and chemical activation or knockdown of NF-кB enhanced or prohibited aggresome assembly. Further analyses showed that NF-кB upregulated HDAC6, and HDAC6 maintained the Vimentin cage by interacting with Vimentin p72, a key modification of the intermediate filament contributing to aggresome formation. Remarkably, chemical inactivation of NF-кB synergized MG132-induced cell mortality. All the findings suggest that NF-кB dictates aggresome assembly via upregulating HDAC6, and NF-кB inhibitor may serve as a potential drug potentiating proteasome inhibitor medicine-induced cytotoxicity during the treatment of cancer cells.<b>NEW & NOTEWORTHY</b> The study reveals a new mechanism guiding MG132-triggered aggresome formation. NF-кB is quickly activated upon exposure to MG132, and NF-кB upregulates the misfolded protein recognizing factor HDCA6. In addition to collecting misfolded proteins, HDAC6 also binds Vimentin and maintains the Vimentin cage, which quarantines toxic misfolded proteins and protects cells from being toxified by those protein toxicants. Therapeutically, chemical inactivation of NF-кB synergizes MG132-induced cytotoxicity, providing a new strategy to defeat cancers.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1289-C1299"},"PeriodicalIF":5.0000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Cell physiology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1152/ajpcell.00671.2023","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/7 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Proteasome inhibitors have been applied to anticancer therapy by accumulating toxic misfolded proteins. However, chemical inactivation of proteasome generates aggresome, a Vimentin cage-enclosed subcellular structure quarantining HDAC6-Dynein-transported misfolded proteins before the protein toxicants are degraded by autophagy. Hence, aggresome may attenuate proteasome inhibitor drug-induced cytotoxicity. To solve the problem, it is imperative to characterize how cells assemble aggresome. By examining aggresomes in six cell lines, A549 cells were selectively studied for their bigger cell size and moderate aggresome-forming activity. Aggresome grew in size upon continuous exposure of A549 cells to proteasome inhibitor MG132 and reached a mature size around the 16th to 24th hour of treatment. Mechanistic studies revealed that NF-кB translocated to the nucleus in MG132-treated cells, and chemical activation or knockdown of NF-кB enhanced or prohibited aggresome assembly. Further analyses showed that NF-кB upregulated HDAC6, and HDAC6 maintained the Vimentin cage by interacting with Vimentin p72, a key modification of the intermediate filament contributing to aggresome formation. Remarkably, chemical inactivation of NF-кB synergized MG132-induced cell mortality. All the findings suggest that NF-кB dictates aggresome assembly via upregulating HDAC6, and NF-кB inhibitor may serve as a potential drug potentiating proteasome inhibitor medicine-induced cytotoxicity during the treatment of cancer cells.NEW & NOTEWORTHY The study reveals a new mechanism guiding MG132-triggered aggresome formation. NF-кB is quickly activated upon exposure to MG132, and NF-кB upregulates the misfolded protein recognizing factor HDCA6. In addition to collecting misfolded proteins, HDAC6 also binds Vimentin and maintains the Vimentin cage, which quarantines toxic misfolded proteins and protects cells from being toxified by those protein toxicants. Therapeutically, chemical inactivation of NF-кB synergizes MG132-induced cytotoxicity, providing a new strategy to defeat cancers.
期刊介绍:
The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.