title: Hypoxia and ER stress promote Staufen1 expression through an alternative translation mechanism.
abstract: Under physiological stress conditions the cell protects itself through a global blockade on cap-dependent translation of mRNA. This allows cap-independent mechanisms such as internal ribosome entry site (IRES)-mediated translation to take over and initiate the translation of a specific pool of mRNAs that encode proteins involved in protecting the cell from stress. Staufen 1 (Stau1) is an RNA-binding protein that has been previously implicated in the regulation of stress granule formation and therefore could play a key role in protecting the cell against stress stimuli such as oxidative and endoplasmic reticulum (ER) stress. We hypothesized that Stau1 mRNA could, like many stress response genes, contain an IRES in its 5'UTR. Here we describe that a bona fide IRES element is present in the 5'UTR of Stau1 mRNA, which is activated under hypoxic and ER stress conditions. Further, we show that the activity of PERK kinase, a major effector of the ER stress response, is required for Stau1 IRES-mediated translation during ER stress. These results suggest that Stau1 is a stress response gene that remains efficiently translated during hypoxia and ER stress despite the substantial global inhibition of cap-dependent protein translation, promoting cell recovery following stress.
authors.affiliation: Inserm U1048, I2MC (Institut des Maladies Métaboliques et Cardiovasculaires), F-31432, Toulouse, France; Université Toulouse III Paul-Sabatier, F-31000, Toulouse, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Bonnet-Magnaval
authors.affiliation: Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), F-31037, Toulouse, France; Université Toulouse III Paul-Sabatier, F-31000, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), F-31037, Toulouse, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Van Den Berghe
authors.affiliation: Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), F-31037, Toulouse, France; Université Toulouse III Paul-Sabatier, F-31000, Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Prats
authors.affiliation: Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), F-31037, Toulouse, France; Université Toulouse III Paul-Sabatier, F-31000, Toulouse, France. Electronic address: christian.touriol@inserm.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Touriol
authors.affiliation: Inserm U1048, I2MC (Institut des Maladies Métaboliques et Cardiovasculaires), F-31432, Toulouse, France; Université Toulouse III Paul-Sabatier, F-31000, Toulouse, France. Electronic address: eric.lacazette@inserm.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Lacazette
mesh_terms: D020121:5' Untranslated Regions; D015687:Cell Hypoxia; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000067556:Internal Ribosome Entry Sites; D009690:Nucleic Acid Conformation; D010100:Oxygen / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D020121:5' Untranslated Regions; D003598:Cytoskeletal Proteins; D000067556:Internal Ribosome Entry Sites; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C492185:STAU1 protein, human; D010100:Oxygen
keywords: Endoplasmic reticulum stress; Hypoxia; IRES (internal ribosome entry site); PERK (PKR-Like endoplasmic reticulum kinase); Stau1 (Staufen 1); UPR (unfolded protein response)