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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >RNA surveillance is required for endoplasmic reticulum homeostasis
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RNA surveillance is required for endoplasmic reticulum homeostasis

机译：内质网稳态需要RNA监测

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摘要

The unfolded protein response (UPR) is an intracellular stress-signaling pathway that counteracts the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Because defects in ER protein folding are associated with many pathological states, including metabolic, neurologic, genetic, and inflammatory diseases, it is important to understand how the UPR maintains ER protein-folding homeostasis. All metazoans have conserved the fundamental UPR transducers IRE1, ATF6, and PERK. In Caenorhabditis elegans, the UPR is required to prevent larval lethality and intestinal degeneration. Although ire-1-null worms are viable, they are particularly sensitive to ER stress. To identify genes that are required for development of ire-7-null worms, we performed a comprehensive RNA interference screen to find 10 genes that exhibit synthetic growth and intestinal defects with the ire-1(v33) mutant but not with atf-6(tm1153) or pek-1(ok27S) mutants. The expression of two of these genes, exos-3 and F48E8.6, was induced by ER stress, and their knockdown in a wild-type strain caused ER stress. Because these genes encode subunits of the exosome complex that functions in mRNA surveillance, we analyzed other gene products required for nonsense-mediated mRNA decay (NMD). Our results demonstrate that defects in smg-1, smg-4, and smg-6 in C. elegans and SMG6 in mammalian cells cause ER stress and sensitize to the lethal effects of ER stress. Although ER stress did not activate mRNA surveillance complex assembly, ER stress did induce SMG6 expression, and NMD regulators were constitutively localized to the ER. Importantly, the findings demonstrate a unique and fundamental interaction where NMD-mediated mRNA quality control is required to prevent ER stress.
机译：展开的蛋白质反应（UPR）是一种细胞内应激信号通路，可抵消错误折叠的蛋白质在内质网（ER）中的积累。由于ER蛋白折叠的缺陷与许多病理状态有关，包括代谢，神经，遗传和炎症性疾病，因此了解UPR如何维持ER蛋白折叠的稳态非常重要。所有后生动物都保留了基本的UPR换能器IRE1，ATF6和PERK。在秀丽隐杆线虫中，需要UPR以防止幼虫致死性和肠道变性。尽管ire-1空蠕虫是可行的，但它们对ER压力特别敏感。为了确定开发ire-7-null蠕虫所需的基因，我们进行了全面的RNA干扰筛选，以找到10个具有ire-1（v33）突变体但不具有atf-6（ tm1153）或pek-1（ok27S）突变体。这些基因中的两个基因exos-3和F48E8.6的表达是由内质网应激诱导的，在野生型菌株中的敲低引起内质网应激。因为这些基因编码在mRNA监测中起作用的外泌体复合物的亚基，所以我们分析了无义介导的mRNA衰变（NMD）所需的其他基因产物。我们的结果表明，哺乳动物细胞中秀丽隐杆线虫和SMG6中smg-1，smg-4和smg-6的缺陷会引起ER应激，并对ER应激的致死作用敏感。尽管内质网应激不会激活mRNA监测复合物装配，但内质网应激确实会诱导SMG6表达，并且NMD调节剂组成性地定位于内质网。重要的是，这些发现证明了独特且基本的相互作用，其中需要NMD介导的mRNA质量控制以防止ER应激。

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    Kenjiro Sakaki; Sawako Yoshina; Xiaohua Shen; Jaeseok Han; Melinda R. DeSantis; Mon Xiong; Shohei Mitani; Randal J. Kaufman;

  • 作者单位

    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Ml 48109,Department of Physiology, Tokyo Women's Medical University School of Medicine, Shinjuku-ku, Tokyo 162-8666, Japan;

    Department of Physiology, Tokyo Women's Medical University School of Medicine, Shinjuku-ku, Tokyo 162-8666, Japan,Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan;

    School of Medicine, Tsinghua University, Beijing 100084, China;

    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Ml 48109,Degenerative Disease Research Program,Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Ml 48109;

    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Ml 48109;

    Department of Physiology, Tokyo Women's Medical University School of Medicine, Shinjuku-ku, Tokyo 162-8666, Japan, Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, Tokyo Women's Medical University Institute for Integrated Medical Science (TIIMS), Shinjuku-ku, Tokyo 162-8666, Japan;

    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Ml 48109, Degenerative Disease Research Program,Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    endoplasmic reticulum quality control; premature termination codons;

    机译：内质网质量控制;提前终止密码子;

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