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


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.

SUBMITTER: Lanna A 

PROVIDER: S-EPMC5321575 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Lanna Alessio A   Gomes Daniel C O DC   Muller-Durovic Bojana B   McDonnell Thomas T   Escors David D   Gilroy Derek W DW   Lee Jun Hee JH   Karin Michael M   Akbar Arne N AN  

Nature immunology 20170123 3


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 individ  ...[more]

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