title: RNA surveillance is required for endoplasmic reticulum homeostasis.
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.
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. sakaki@research.twmu.ac.jp
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sakaki
authors.forename: Sawako
authors.initials: S
authors.lastname: Yoshina
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Shen
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Han
authors.forename: Melinda R
authors.initials: MR
authors.lastname: DeSantis
authors.forename: Mon
authors.initials: M
authors.lastname: Xiong
authors.forename: Shohei
authors.initials: S
authors.lastname: Mitani
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000502:physiology; D018389:Codon, Nonsense / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006367:HeLa Cells; D022781:Hepatocytes / Q000166:cytology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007814:Larva / Q000502:physiology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology; D016601:RNA-Binding Proteins; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism; D004722:Endoribonucleases
chemical_list: D029742:Caenorhabditis elegans Proteins; D018389:Codon, Nonsense; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012313:RNA; D016601:RNA-Binding Proteins; D019098:Telomerase; D019892:eIF-2 Kinase; C431142:Smg-4 protein, C elegans; C490966:SMG-1 protein, C elegans; C541905:IRE-1 protein, C elegans; C512261:SMG6 protein, human; D004722:Endoribonucleases