RRC ID 46490
Author Sakaki K, Yoshina S, Shen X, Han J, DeSantis MR, Xiong M, Mitani S, Kaufman RJ.
Title RNA surveillance is required for endoplasmic reticulum homeostasis.
Journal Proc Natl Acad Sci U S A
Abstract 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 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.
Volume 109(21)
Pages 8079-84
Published 2012-5-22
DOI 10.1073/pnas.1110589109
PII 1110589109
PMID 22562797
PMC PMC3361423
MeSH Animals Animals, Genetically Modified Caenorhabditis elegans / genetics* Caenorhabditis elegans / growth & development Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Caenorhabditis elegans Proteins / physiology Cell Line, Transformed Cell Survival / physiology Codon, Nonsense / genetics Endoplasmic Reticulum / physiology* Endoplasmic Reticulum Stress / physiology* HeLa Cells Hepatocytes / cytology Homeostasis / physiology* Humans Larva / physiology Mice Nuclear Proteins / genetics Nuclear Proteins / metabolism Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Proteostasis Deficiencies / genetics Proteostasis Deficiencies / metabolism RNA / genetics* RNA Interference / physiology RNA-Binding Proteins Telomerase / genetics Telomerase / metabolism Unfolded Protein Response / genetics* eIF-2 Kinase / genetics eIF-2 Kinase / metabolism
IF 9.412
Times Cited 46
C.elegans tm1153 tm849 tm5409