The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells.

Abstract:

:In T lymphocytes, the mitogen-activated protein kinase (MAPK) p38 regulates pleiotropic functions and is activated by canonical MAPK signaling or the alternative activation pathway downstream of the T cell antigen receptor (TCR). Here we found that senescent human T cells lacked the canonical and alternative pathways for the activation of p38 but spontaneously engaged the metabolic master regulator AMPK to trigger recruitment of p38 to the scaffold protein TAB1, which caused autophosphorylation of p38. Signaling via this pathway inhibited telomerase activity, T cell proliferation and the expression of key components of the TCR signalosome. Our findings identify a previously unrecognized mode for the activation of p38 in T cells driven by intracellular changes such as low-nutrient and DNA-damage signaling (an 'intrasensory' pathway). The proliferative defect of senescent T cells was reversed by blockade of AMPK-TAB1-dependent activation of p38.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

Lanna A,Henson SM,Escors D,Akbar AN

doi

10.1038/ni.2981

subject

Has Abstract

pub_date

2014-10-01 00:00:00

pages

965-72

issue

10

eissn

1529-2908

issn

1529-2916

pii

ni.2981

journal_volume

15

pub_type

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