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Nat Immunol. 2017 Mar;18(3):354-363. doi: 10.1038/ni.3665. Epub 2017 Jan 23.

A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging.

Author information

1
Division of Infection and Immunity, University College London, London, UK.
2
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
3
Núcleo de Doenças Infecciosas/Núcleo de Biotecnologia, Universidade Federal do Espírito Santo - UFES, Vitória, Brazil.
4
Navarrabiomed-Biomedical Research Centre, Fundación Miguel Servet, IdisNA, Complejo Hospitalario de Navarra, Pamplona, Spain.
5
Division of Medicine, University College London, London, London, UK.
6
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
7
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego School of Medicine, La Jolla, California, USA.

Abstract

Mitogen-activated protein kinases (MAPKs) including Erk, Jnk and p38 regulate diverse cellular functions and are thought to be controlled by independent upstream activation cascades. Here we show that the sestrins bind to and coordinate simultaneous Erk, Jnk and p38 MAPK activation in T lymphocytes within a new immune-inhibitory complex (sestrin-MAPK activation complex (sMAC)). Whereas sestrin ablation resulted in broad reconstitution of immune function in stressed T cells, inhibition of individual MAPKs allowed only partial functional recovery. T cells from old humans (>65 years old) or mice (16-20 months old) were more likely to form the sMAC, and disruption of this complex restored antigen-specific functional responses in these cells. Correspondingly, sestrin deficiency or simultaneous inhibition of all three MAPKs enhanced vaccine responsiveness in old mice. Thus, disruption of sMAC provides a foundation for rejuvenating immunity during aging.

PMID:
28114291
PMCID:
PMC5321575
DOI:
10.1038/ni.3665
[Indexed for MEDLINE]
Free PMC Article

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