mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.
Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Nicolás
N
Herranz
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Metabolic Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Suchira
S
Gallage
Cancer Sciences Unit, Cancer Research UK Centre, Somers Building, University of Southampton, Southampton SO16 6YD, UK.
Massimiliano
M
Mellone
Division of Molecular Oncology of Solid Tumors, Department of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Torsten
T
Wuestefeld
Division of Molecular Oncology of Solid Tumors, Department of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Sabrina
S
Klotz
Cancer Sciences Unit, Cancer Research UK Centre, Somers Building, University of Southampton, Southampton SO16 6YD, UK.
Christopher J
CJ
Hanley
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Selina
S
Raguz
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Juan Carlos
JC
Acosta
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Andrew J
AJ
Innes
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Ana
A
Banito
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Athena
A
Georgilis
Proteomics Facility, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Alex
A
Montoya
Division of Molecular Oncology of Solid Tumors, Department of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Katharina
K
Wolter
Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Gopuraja
G
Dharmalingam
Proteomics Facility, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Peter
P
Faull
Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Thomas
T
Carroll
Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London WC1N 1EH, UK.
Juan Pedro
JP
Martínez-Barbera
Proteomics Facility, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Pedro
P
Cutillas
Institute for Virology, Technische Universität München/Helmholtz Zentrum München, 81675 Munich, Germany.
Florian
F
Reisinger
Institute for Virology, Technische Universität München/Helmholtz Zentrum München, 81675 Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research (DKFZ), 69121 Heidelberg, Germany.
Mathias
M
Heikenwalder
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan 48109-2200, USA.
Richard A
RA
Miller
Metabolic Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Dominic
D
Withers
Division of Molecular Oncology of Solid Tumors, Department of Internal Medicine I, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Lars
L
Zender
Cancer Sciences Unit, Cancer Research UK Centre, Somers Building, University of Southampton, Southampton SO16 6YD, UK.
Gareth J
GJ
Thomas
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Epigenetics Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Jesús
J
Gil
D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000378:metabolism*; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D000099190:MAP-Kinase-Activated Kinase 2
D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D020543:Proteome; D058570:TOR Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C546842:MTOR protein, human