Hypoxia regulates overall mRNA homeostasis by inducing Met1-linked linear ubiquitination of AGO2 in cancer cells

• Published in: Nature communications Vol. 12; no. 1; p. 5416
• Main Authors: Zhang, Hailong, Zhao, Xian, Guo, Yanmin, Chen, Ran, He, Jianfeng, Li, Lian, Qiang, Zhe, Yang, Qianqian, Liu, Xiaojia, Huang, Caihu, Lu, Runhui, Fang, Jiayu, Cao, Yingting, Huang, Jiayi, Wang, Yanli, Huang, Jian, Chen, Guo-Qiang, Cheng, Jinke, Yu, Jianxiu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-09-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/89; 14/19; 38/39; 38/71; 38/77; 38/91; 45/90; 631/45/500; 631/67; 631/80/458/582; 82/58; 82/83; Argonaute 2 protein; Assembly; Cancer; Chains; Gene expression; Gene silencing; Homeostasis; Humanities and Social Sciences; Hypoxia; Hypoxia-inducible factors; miRNA; mRNA turnover; multidisciplinary; Proteins; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Solid tumors; Transcriptomes; Tumor cells; Tumors; Ubiquitin; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25739-5

Hypoxia is the most prominent feature in human solid tumors and induces activation of hypoxia-inducible factors and their downstream genes to promote cancer progression. However, whether and how hypoxia regulates overall mRNA homeostasis is unclear. Here we show that hypoxia inhibits global-mRNA decay in cancer cells. Mechanistically, hypoxia induces the interaction of AGO2 with LUBAC, the linear ubiquitin chain assembly complex, which co-localizes with miRNA-induced silencing complex and in turn catalyzes AGO2 occurring Met
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-linked linear ubiquitination (M1-Ubi). A series of biochemical experiments reveal that M1-Ubi of AGO2 restrains miRNA-mediated gene silencing. Moreover, combination analyses of the AGO2-associated mRNA transcriptome by RIP-Seq and the mRNA transcriptome by RNA-Seq confirm that AGO2 M1-Ubi interferes miRNA-targeted mRNA recruiting to AGO2, and thereby facilitates accumulation of global mRNAs. By this mechanism, short-term hypoxia may protect overall mRNAs and enhances stress tolerance, whereas long-term hypoxia in tumor cells results in seriously changing the entire gene expression profile to drive cell malignant evolution.
Met
1
-linked linear ubiquitination (M
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-Ubi) is catalyzed by linear ubiquitin chain assembly complex (LUBAC). Here the authors show that Ago2 protein is M
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-Ubi modified by LUBAC complex under hypoxia condition leading to less association of miRNA target mRNAs to Ago2 protein and de-repression of miRNA targets.