title: Assessment of mTOR-Dependent Translational Regulation of Interferon Stimulated Genes.
abstract: Type-I interferon (IFN)-induced activation of the mammalian target of rapamycin (mTOR) signaling pathway has been implicated in translational control of mRNAs encoding interferon-stimulated genes (ISGs). However, mTOR-sensitive translatomes commonly include mRNAs with a 5' terminal oligopyrimidine tract (TOP), such as those encoding ribosomal proteins, but not ISGs. Because these translatomes were obtained under conditions when ISG expression is not induced, we examined the mTOR-sensitive translatome in human WISH cells stimulated with IFN β. The mTOR inhibitor Torin1 resulted in a repression of global protein synthesis, including that of ISG products, and translation of all but 3 ISG mRNAs (TLR3, NT5C3A, and RNF19B) was not selectively more sensitive to mTOR inhibition. Detailed studies of NT5C3A revealed an IFN-induced change in transcription start site resulting in a switch from a non-TOP to a TOP-like transcript variant and mTOR sensitive translation. Thus, we show that, in the cell model used, translation of the vast majority of ISG mRNAs is not selectively sensitive to mTOR activity and describe an uncharacterized mechanism wherein the 5'-UTR of an mRNA is altered in response to a cytokine, resulting in a shift from mTOR-insensitive to mTOR-sensitive translation.
authors.affiliation: Cytokine Signaling Unit, Institut Pasteur, CNRS URA1961, Paris, France.
authors.forename: Mark
authors.initials: M
authors.lastname: Livingstone
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sikström
authors.affiliation: Cytokine Signaling Unit, Institut Pasteur, CNRS URA1961, Paris, France.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Robert
authors.affiliation: CNRS UMR5235, University of Montpellier II, Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Uzé
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Cytokine Signaling Unit, Institut Pasteur, CNRS URA1961, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pellegrini
mesh_terms: D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D009287:Naphthyridines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D009287:Naphthyridines; D016899:Interferon-beta; D058570:TOR Serine-Threonine Kinases