Hypoxia regulates overall mRNA homeostasis by inducing Met(1)-linked linear ubiquitination of AGO2 in cancer cells.
Hypoxia regulates overall mRNA homeostasis by inducing Met(1)-linked linear ubiquitination of AGO2 in cancer cells.
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缺氧通过诱导癌细胞中 AGO2 的 Met1 相关线性泛素化来调节整体 mRNA 稳态
DOI：
10.1038/s41467-021-25739-5
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发表时间：
2021-09-13
影响因子：
16.6
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Zhang H;Zhao X;Guo Y;Chen R;He J;Li L;Qiang Z;Yang Q;Liu X;Huang C;Lu R;Fang J;Cao Y;Huang J;Wang Y;Huang J;Chen GQ;Cheng J;Yu J
低氧是人类实体瘤最显著的特征，可诱导低氧诱导因子及其下游基因的激活，从而促进肿瘤的进展。然而，低氧是否以及如何调节整体的mRNA动态平衡尚不清楚。在这里，我们展示了低氧抑制癌细胞中全局-信使核糖核酸的衰退。从机制上讲，缺氧诱导AGO2与LUBAC的相互作用，LUBAC与miRNA诱导的沉默复合体共定位，进而催化AGO2发生MET1连接的线性泛素化(M1-Ubi)。一系列生化实验表明，AGO2的M1-Ubi抑制miRNA介导的基因沉默。此外，RIP-Seq对AGO2相关mRNA转录组和RNA-Seq mRNA转录组的联合分析证实，AGO2 M1-Ubi干扰了miRNA靶向AGO2的mRNA募集，从而促进了全局mRNAs的积累。通过这一机制，短期低氧可能保护整体mRNAs，提高应激耐受性，而长期低氧会导致肿瘤细胞整个基因表达谱严重改变，从而推动细胞恶性进化。MET1连接的线性泛素化(M1-Ubi)是由线性泛素链组装复合体(LUBAC)催化的。在此，作者证明了在低氧条件下，Ago2蛋白是由LUBAC复合体修饰的M1-Ubi，导致miRNA靶标mRNAs与Ago2蛋白结合较少，从而降低了miRNA靶标的表达。
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 Met1-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. Met1-linked linear ubiquitination (M1-Ubi) is catalyzed by linear ubiquitin chain assembly complex (LUBAC). Here the authors show that Ago2 protein is M1-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.
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影响因子：
16
作者：
Leung AK;Sharp PA
通讯作者：
Sharp PA
癌症中的microRNA生物发生途径。
DOI：
10.1038/nrc3932
发表时间：
2015-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Lin S;Gregory RI
通讯作者：
Gregory RI
影响因子：
64.8
作者：
Ikeda, Fumiyo;Deribe, Yonathan Lissanu;Skanland, Sigrid S.;Stieglitz, Benjamin;Grabbe, Caroline;Franz-Wachtel, Mirita;van Wijk, Sjoerd J. L.;Goswami, Panchali;Nagy, Vanja;Terzic, Janos;Tokunaga, Fuminori;Androulidaki, Ariadne;Nakagawa, Tomoko;Pasparakis, Manolis;Iwai, Kazuhiro;Sundberg, John P.;Schaefer, Liliana;Rittinger, Katrin;Macek, Boris;Dikic, Ivan
通讯作者：
Dikic, Ivan
DOI：
10.1126/science.1190809
发表时间：
2010-06-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cifuentes D;Xue H;Taylor DW;Patnode H;Mishima Y;Cheloufi S;Ma E;Mane S;Hannon GJ;Lawson ND;Wolfe SA;Giraldez AJ
通讯作者：
Giraldez AJ
影响因子：
16
作者：
Horman, Shane R.;Janas, Maja M.;Litterst, Claudia;Wang, Bingbing;MacRae, Ian J.;Sever, Mary J.;Morrissey, David V.;Graves, Paul;Luo, Biao;Umesalma, Shaikamjad;Qi, Hank H.;Miraglia, Loren J.;Novina, Carl D.;Orth, Anthony P.
通讯作者：
Orth, Anthony P.