SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay
SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay
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DOI：
10.1101/gad.1767209
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发表时间：
2009-05-01
影响因子：
10.5
通讯作者：
Ohno, Shigeo
中科院分区：
文献类型：
--
作者：
Yamashita, Akio;Izumi, Natsuko;Ohno, Shigeo
无义介导的mRNA衰变（NMD）是一种检测和降解含有过早翻译终止密码子（PTC）的mRNA的监视机制。SMG-1和Upf 1在PTC识别过程中瞬时形成称为“SURF”的监视复合物，该复合物包括剪接后mRNA上的eRF 1和eRF 3。如果SURF复合物下游存在外显子连接复合物（EJC），SMG-1会磷酸化Upf 1，这是NMD的限速步骤。我们提供的证据SURF复合物和核糖体之间的关联与mRNP，我们建议，SURF复合物的功能作为一个翻译终止复合物在NMD。我们鉴定了SMG-8和SMG-9作为SMG-1复合物的新亚基。SMG-8和SMG-9抑制分离的SMG-1复合物中的SMG-1激酶活性，并参与哺乳动物和线虫的NMD。SMG-8将SMG-1募集到mRNA监视复合物中，SMG-8的失活诱导核糖体：Upf 1：eRF 1：eRF 3：EJC复合物在mRNP上的积累，该复合物通过eRF 1、eRF 3和Upf 1物理桥接核糖体和EJC。这些结果不仅揭示了SMG-1激酶的调节机制，而且揭示了核糖体：SURF复合物向预测的DECID（DECay Inducing）复合物（核糖体：SURF：EJC复合物）的连续重塑，作为体内PTC辨别的机制。
Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades mRNAs containing premature translation termination codons (PTCs). SMG-1 and Upf1 transiently form a surveillance complex termed "SURF'' that includes eRF1 and eRF3 on post-spliced mRNAs during recognition of PTC. If an exon junction complex (EJC) exists downstream from the SURF complex, SMG-1 phosphorylates Upf1, the step that is a rate-limiting for NMD. We provide evidence of an association between the SURF complex and the ribosome in association with mRNPs, and we suggest that the SURF complex functions as a translation termination complex during NMD. We identified SMG-8 and SMG-9 as novel subunits of the SMG-1 complex. SMG-8 and SMG-9 suppress SMG-1 kinase activity in the isolated SMG-1 complex and are involved in NMD in both mammals and nematodes. SMG-8 recruits SMG-1 to the mRNA surveillance complex, and inactivation of SMG-8 induces accumulation of a ribosome: Upf1: eRF1: eRF3: EJC complex on mRNP, which physically bridges the ribosome and EJC through eRF1, eRF3, and Upf1. These results not only reveal the regulatory mechanism of SMG-1 kinase but also reveal the sequential remodeling of the ribosome: SURF complex to the predicted DECID (DECay InDucing) complex, a ribosome: SURF: EJC complex, as a mechanism of in vivo PTC discrimination.