ZRF1 is a novel S6 kinase substrate that drives the senescence programme

被引:30
作者
Barilari, Manuela [1 ,2 ,3 ]
Bonfils, Gregory [1 ,2 ,3 ]
Treins, Caroline [1 ,2 ,3 ]
Koka, Vonda [1 ,2 ,3 ]
De Villeneuve, Delphine [1 ,2 ,3 ]
Fabrega, Sylvie [4 ]
Pende, Mario [1 ,2 ,3 ]
机构
[1] Inst Necker Enfants Malad, Paris, France
[2] INSERM, U1151, Paris, France
[3] Univ Paris 05, Sorbonne Paris Cite, Paris, France
[4] Hop Necker Enfants Malad, IFR94, Plateforme Vecteurs Viraux & Transfert Genes, Paris, France
基金
欧洲研究理事会;
关键词
mTOR; senescence; S6; kinase; tuberous sclerosis complex; ZRF1; TRANSLATIONAL CONTROL; CELLULAR SENESCENCE; PROTEIN-KINASE; STEM-CELLS; LIFE-SPAN; MTOR; GROWTH; MICE; REVEALS; PHENOTYPE;
D O I
10.15252/embj.201694966
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 tissues in vivo. Knockdown of ZRF1 or expression of a phosphorylation mutant is sufficient to blunt the S6 kinasedependent 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 mTORC1S6 kinases and the phosphorylation of ZRF1.
引用
收藏
页码:736 / 750
页数:15
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