A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging.
A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging.
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DOI：
10.1038/ni.3665
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发表时间：
2017-03
影响因子：
30.5
通讯作者：
Akbar AN
中科院分区：
文献类型：
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作者：
Lanna A;Gomes DC;Muller-Durovic B;McDonnell T;Escors D;Gilroy DW;Lee JH;Karin M;Akbar AN
丝裂原活化蛋白激酶(MAPK)包括ERK、JNK和p38，调节多种细胞功能，被认为是由独立的上游激活级联反应控制的。在这里，我们发现Sestrins在一种新的免疫抑制复合体(Sestrin-MAPK激活复合体；SMAC)中与T淋巴细胞中同时激活的Erk、JNK和p38MAPK结合并协调。然而，Sestrin消融导致应激T细胞免疫功能的广泛重建，而抑制单个MAPK只能使部分功能恢复。来自老年人和小鼠的T细胞更有可能形成SMAC，破坏这种复合体可以恢复这些细胞中的抗原特异性功能反应。相应地，Sestrin缺乏或同时抑制所有三种MAPK会增强老年小鼠的疫苗反应性。因此，Smac的破坏为衰老期间恢复免疫力提供了基础。
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 co-ordinate 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 only allowed partial functional recovery. T cells from old humans and mice 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 ageing.