RNA surveillance is required for endoplasmic reticulum homeostasis

被引:68
|
作者
Sakaki, Kenjiro [1 ,2 ]
Yoshina, Sawako [2 ,3 ]
Shen, Xiaohua [4 ]
Han, Jaeseok [1 ,5 ]
DeSantis, Melinda R. [1 ]
Xiong, Mon [1 ]
Mitani, Shohei [2 ,3 ,6 ]
Kaufman, Randal J. [1 ,5 ]
机构
[1] Univ Michigan, Dept Biol Chem, Med Ctr, Ann Arbor, MI 48109 USA
[2] Tokyo Womens Med Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo 1628666, Japan
[3] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Kawaguchi, Saitama 3320012, Japan
[4] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China
[5] Sanford Burnham Med Res Inst, Degenerat Dis Res Program, Aging & Stem Cell Res Ctr, La Jolla, CA 92037 USA
[6] Tokyo Womens Med Univ, Inst Integrated Med Sci TIIMS, Shinjuku Ku, Tokyo 1628666, Japan
基金
美国国家卫生研究院; 日本学术振兴会;
关键词
endoplasmic reticulum quality control; premature termination codons; UNFOLDED PROTEIN RESPONSE; NF-KAPPA-B; MESSENGER-RNA; CAENORHABDITIS-ELEGANS; QUALITY-CONTROL; UPF1; PHOSPHORYLATION; MAMMALIAN-CELLS; STRESS; ATF6; ACTIVATION;
D O I
10.1073/pnas.1110589109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
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-1-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(ok275) mutants. The expression of two of these genes, exos-3 and F48E8.6, was induced by ER stress, and their knockdown in a wildtype 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-mediatedm RNA quality control is required to prevent ER stress.
引用
收藏
页码:8079 / 8084
页数:6
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