A sestrin-dependent Erk/Jnk/p38 MAPK activation complex inhibits immunity during ageing
| Autor: | Thomas McDonnell, Bojana Müller-Durovic, Michael Karin, Arne N. Akbar, Jun Hee Lee, Alessio Lanna, David Escors, Daniel Cláudio de Oliveira Gomes, Derek W. Gilroy |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Adult CD4-Positive T-Lymphocytes Male Aging Immunosenescence MAP Kinase Kinase 4 p38 mitogen-activated protein kinases Immunology Biology Article 03 medical and health sciences Mice Young Adult Immune system Immunity Heat shock protein Immunology and Allergy Animals Humans RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Cells Cultured Heat-Shock Proteins Aged Aged 80 and over Kinase Middle Aged Acquired immune system Cell biology 030104 developmental biology Female Signal transduction Signal Transduction |
| Zdroj: | Nature immunology |
| DOI: | 10.1038/ni.3665 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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