ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay.
ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay.
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DOI：
10.1038/nsmb.3403
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发表时间：
2017-06
影响因子：
16.8
通讯作者：
Nishikura K
中科院分区：
文献类型：
--
作者：
Sakurai M;Shiromoto Y;Ota H;Song C;Kossenkov AV;Wickramasinghe J;Showe LC;Skordalakes E;Tang HY;Speicher DW;Nishikura K
ADAR1 的 p150 和 p110 亚型均可将双链 RNA (dsRNA) 中的腺苷转化为肌苷。 ADAR1p150 抑制激活细胞质中 MDA5-MAVS-IFN 信号传导的 dsRNA 传感机制。相比之下，ADAR1p110 亚型（通常位于细胞核）的生物学功能仍然很大程度上未知。在这里，我们表明 MKK6-p38-MSK MAP 激酶对 ADAR1p110 的应激激活磷酸化促进其与 Exportin-5 结合并从细胞核输出。一旦转位到细胞质，ADAR1p110 通过保护许多含有主要由反向 Alu 重复组成的 3'UTR dsRNA 结构的抗凋亡基因转录本来抑制应激细胞的凋亡。 ADAR1p110 竞争性抑制 Staufen1 与 3'UTR dsRNA 的结合，并拮抗 Staufen1 介导的 mRNA 衰减。我们的研究揭示了一种新的应激反应机制，其中人类 ADAR1p110 和 Staufen1 调节对应激细胞生存所需的一组 mRNA 的监视。
Both p150 and p110 isoforms of ADAR1 convert adenosine to inosine in double-stranded RNA (dsRNA). ADAR1p150 suppresses the dsRNA sensing mechanism that activates MDA5-MAVS-IFN signaling in the cytoplasm. In contrast, the biological function of the ADAR1p110 isoform, usually located in the nucleus, remains largely unknown. Here we show that stress-activated phosphorylation of ADAR1p110 by MKK6-p38-MSK MAP kinases promotes its binding to Exportin-5 and export from the nucleus. Once translocated to the cytoplasm, ADAR1p110 suppresses apoptosis of stressed cells by protecting many anti-apoptotic gene transcripts that contain 3′UTR dsRNA structures primarily made from inverted Alu repeats. ADAR1p110 competitively inhibits binding of Staufen1 to the 3′UTR dsRNAs and antagonizes the Staufen1-mediated mRNA decay. Our studies revealed a new stress response mechanism, in which human ADAR1p110 and Staufen1 regulate surveillance of a set of mRNAs required for survival of stressed cells.