title: The cold-inducible RNA-binding protein migrates from the nucleus to cytoplasmic stress granules by a methylation-dependent mechanism and acts as a translational repressor.
abstract: The cold-inducible RNA-binding protein (CIRP) is a nuclear 18-kDa protein consisting of an amino-terminal RNA Recognition Motif (RRM) and a carboxyl-terminal domain containing several RGG motifs. First characterized for its overexpression upon cold shock, CIRP is also induced by stresses such as UV irradiation and hypoxia. Here, we investigated the expression as well as the subcellular localization of CIRP in response to other stress conditions. We demonstrate that oxidative stress leads to the migration of CIRP to stress granules (SGs) without alteration of expression. Stress granules are dynamic cytoplasmic foci at which stalled translation initiation complexes accumulate in cells subjected to environmental stress. Relocalization of CIRP into SGs also occurs upon other cytoplasmic stresses (osmotic pressure or heat shock) as well as in response to stresses of the endoplasmic reticulum. CIRP migration into SGs is independent from TIA-1 which has been previously reported to be a general mediator of SG formation, thereby suggesting the existence of multiple pathways leading to SG formation. Moreover, deletion mutants revealed that both RGG and RRM domains can independently promote CIRP migration into SGs. However, the methylation of arginine residues in the RGG domain is necessary for CIRP to exit the nucleus to be further recruited into SGs. By RNA-tethering experiments, we also show that CIRP down-regulates mRNA translation and that this activity is carried by the carboxyl-terminal RG-enriched domain. Altogether, our findings further reveal the diversity of mechanisms by which CIRP is regulated by environmental stresses and provide new insights into CIRP cytoplasmic function.
authors.affiliation: Laboratoire de Chimie Biologique, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, 12 rue des Profs. Jeener et Brachet, 6041 Gosselies, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: De Leeuw
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Corinne
authors.initials: C
authors.lastname: Wauquier
authors.forename: Georges
authors.initials: G
authors.lastname: Huez
authors.forename: Véronique
authors.initials: V
authors.lastname: Kruys
authors.forename: Cyril
authors.initials: C
authors.lastname: Gueydan
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D020816:Amino Acid Motifs; D000818:Animals; D001120:Arginine; D018053:Arsenites / Q000494:pharmacology; D019556:COS Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008745:Methylation / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D014176:Protein Biosynthesis / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D000074019:T-Cell Intracellular Antigen-1
chemical_list: D018053:Arsenites; C106176:Cirbp protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D000074019:T-Cell Intracellular Antigen-1; C499367:Tia1 protein, mouse; D001120:Arginine; C015001:arsenite