{"title":"E3连接酶TRIM21下调导致的OAS3去泛素化促进上皮细胞凋亡并驱动败血症诱发的急性肺损伤","authors":"Zhenfeng Chen, Bingqi Lin, Xiaodan Yao, Yihang Fang, Jinlian Liu, Ke Song, Lina Tuolihong, Zirui Zuo, Qi He, Xiaoxia Huang, Zhuanhua Liu, Qiaobing Huang, Qiulin Xu, Zhifeng Liu, Xiaohua Guo","doi":"10.7150/ijbs.96089","DOIUrl":null,"url":null,"abstract":"<p><p>Patients with sepsis-induced acute lung injury (SALI) show a high mortality rate, and there is no effective treatment in the clinic for SALI but only symptomatic treatment as an option. Therefore, searching for effective targets is critical for the management of SALI. Ubiquitination is an essential post-translational protein modification involved in most pathophysiological processes. However, the relationship between ubiquitination and SALI remains largely unclear. In this study, we examined the ubiquitination modification changes in SALI, identified oligoadenylate synthetase 3 (OAS3) as a key candidate accounting for SALI from integrative multi-omics analysis and confirmed its role in promoting SALI and cell apoptosis in an animal model of cecal ligation and puncture-treated mice and a cellular model of LPS-treated MLE12 cells. Mechanistically, downregulation of E3 ligase TRIM21 mediates the reduction of OAS3 K48-linked polyubiquitination at the K1079 site in lung epithelial cells of a septic model, which leads to the increase of OAS3 protein level in a proteasomal-dependent manner. The upregulated OAS3 promotes epithelial cell apoptosis through its downstream effector molecule, RNase L. In summary, these findings unveil a previously unappreciated role of OAS3 ubiquitination in SALI and offer a promising perspective for further understanding the development of sepsis and potential therapeutic target for the treatment of SALI.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 14","pages":"5594-5607"},"PeriodicalIF":8.2000,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528449/pdf/","citationCount":"0","resultStr":"{\"title\":\"OAS3 Deubiquitination Due to E3 Ligase TRIM21 Downregulation Promotes Epithelial Cell Apoptosis and Drives Sepsis-induced Acute Lung Injury.\",\"authors\":\"Zhenfeng Chen, Bingqi Lin, Xiaodan Yao, Yihang Fang, Jinlian Liu, Ke Song, Lina Tuolihong, Zirui Zuo, Qi He, Xiaoxia Huang, Zhuanhua Liu, Qiaobing Huang, Qiulin Xu, Zhifeng Liu, Xiaohua Guo\",\"doi\":\"10.7150/ijbs.96089\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Patients with sepsis-induced acute lung injury (SALI) show a high mortality rate, and there is no effective treatment in the clinic for SALI but only symptomatic treatment as an option. Therefore, searching for effective targets is critical for the management of SALI. Ubiquitination is an essential post-translational protein modification involved in most pathophysiological processes. However, the relationship between ubiquitination and SALI remains largely unclear. In this study, we examined the ubiquitination modification changes in SALI, identified oligoadenylate synthetase 3 (OAS3) as a key candidate accounting for SALI from integrative multi-omics analysis and confirmed its role in promoting SALI and cell apoptosis in an animal model of cecal ligation and puncture-treated mice and a cellular model of LPS-treated MLE12 cells. Mechanistically, downregulation of E3 ligase TRIM21 mediates the reduction of OAS3 K48-linked polyubiquitination at the K1079 site in lung epithelial cells of a septic model, which leads to the increase of OAS3 protein level in a proteasomal-dependent manner. The upregulated OAS3 promotes epithelial cell apoptosis through its downstream effector molecule, RNase L. In summary, these findings unveil a previously unappreciated role of OAS3 ubiquitination in SALI and offer a promising perspective for further understanding the development of sepsis and potential therapeutic target for the treatment of SALI.</p>\",\"PeriodicalId\":13762,\"journal\":{\"name\":\"International Journal of Biological Sciences\",\"volume\":\"20 14\",\"pages\":\"5594-5607\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2024-10-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528449/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Biological Sciences\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.7150/ijbs.96089\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Biological Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.7150/ijbs.96089","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
OAS3 Deubiquitination Due to E3 Ligase TRIM21 Downregulation Promotes Epithelial Cell Apoptosis and Drives Sepsis-induced Acute Lung Injury.
Patients with sepsis-induced acute lung injury (SALI) show a high mortality rate, and there is no effective treatment in the clinic for SALI but only symptomatic treatment as an option. Therefore, searching for effective targets is critical for the management of SALI. Ubiquitination is an essential post-translational protein modification involved in most pathophysiological processes. However, the relationship between ubiquitination and SALI remains largely unclear. In this study, we examined the ubiquitination modification changes in SALI, identified oligoadenylate synthetase 3 (OAS3) as a key candidate accounting for SALI from integrative multi-omics analysis and confirmed its role in promoting SALI and cell apoptosis in an animal model of cecal ligation and puncture-treated mice and a cellular model of LPS-treated MLE12 cells. Mechanistically, downregulation of E3 ligase TRIM21 mediates the reduction of OAS3 K48-linked polyubiquitination at the K1079 site in lung epithelial cells of a septic model, which leads to the increase of OAS3 protein level in a proteasomal-dependent manner. The upregulated OAS3 promotes epithelial cell apoptosis through its downstream effector molecule, RNase L. In summary, these findings unveil a previously unappreciated role of OAS3 ubiquitination in SALI and offer a promising perspective for further understanding the development of sepsis and potential therapeutic target for the treatment of SALI.
期刊介绍:
The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.