title: ZRF1 is a novel S6 kinase substrate that drives the senescence programme.
abstract: The inactivation of S6 kinases mimics several aspects of caloric restriction, including small body size, increased insulin sensitivity and longevity. However, the impact of S6 kinase activity on cellular senescence remains to be established. Here, we show that the constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) by tuberous sclerosis complex (TSC) mutations induces a premature senescence programme in fibroblasts that relies on S6 kinases. To determine novel molecular targets linking S6 kinase activation to the control of senescence, we set up a chemical genetic screen, leading to the identification of the nuclear epigenetic factor ZRF1 (also known as DNAJC2, MIDA1, Mpp11). S6 kinases phosphorylate ZRF1 on Ser47 in cultured cells and in mammalian tissuesin vivoKnock-down of ZRF1 or expression of a phosphorylation mutant is sufficient to blunt the S6 kinase-dependent senescence programme. This is traced by a sharp alteration in p16 levels, the cell cycle inhibitor and a master regulator of senescence. Our findings reveal a mechanism by which nutrient sensing pathways impact on cell senescence through the activation of mTORC1-S6 kinases and the phosphorylation of ZRF1.
authors.affiliation: Institut Necker-Enfants Malades, Paris, France.|Inserm, U1151, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Manuela
authors.initials: M
authors.lastname: Barilari
authors.affiliation: Institut Necker-Enfants Malades, Paris, France.|Inserm, U1151, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Bonfils
authors.affiliation: Institut Necker-Enfants Malades, Paris, France.|Inserm, U1151, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Treins
authors.affiliation: Institut Necker-Enfants Malades, Paris, France.|Inserm, U1151, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Vonda
authors.initials: V
authors.lastname: Koka
authors.affiliation: Institut Necker-Enfants Malades, Paris, France.|Inserm, U1151, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: De Villeneuve
authors.affiliation: Plateforme Vecteurs Viraux et Transfert de Gènes, IFR94, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fabrega
authors.affiliation: Institut Necker-Enfants Malades, Paris, France mario.pende@inserm.fr.|Inserm, U1151, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Mario
authors.identifier: 0000-0002-7864-8937
authors.initials: M
authors.lastname: Pende
mesh_terms: D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016601:RNA-Binding Proteins; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C097474:Dnajc2 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D016601:RNA-Binding Proteins; D019893:Ribosomal Protein S6 Kinases
keywords: S6 kinase; ZRF1; mTOR; senescence; tuberous sclerosis complex