Genetic disruption of p38α Tyr323 phosphorylation prevents T-cell receptor–mediated p38α activation and impairs interferon-γ production

Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation

“…To understand the biologic significance of the alternative p38 activation pathway in vivo, we created knockin mice in which a Tyr-to-Phe substitution was introduced at p38␣ residue 323 (p38␣ Y323F ). 8 This mutation abolished p38␣ activation via TCR signaling without affecting canonical MAPK cascade-induced activation. Lack of TCR-induced p38␣ activity led to a modest but reproducible delay in the onset of T-cell proliferation and decreased production of inflammatory cytokines, such as IFN-␥ and TNF-␣.…”

“…p38␣ Y323F CD4 ϩ T cells could be skewed to Th1 cells in vivo, but these effector cells produced less IFN-␥ than wild-type (WT) Th1 cells when stimulated via the TCR. 8 In resting T cells, p38 activity is inhibited by Gadd45␣, genetic disruption of which results in constitutive up-regulation of the T cell alternative p38 activation pathway, with hyperproliferation in response to TCR-mediated signals and spontaneous development of lupus-like autoimmunity. 9 Gadd45␣ binds p38 and inhibits kinase activity induced by Tyr-323 phosphorylation.…”

The p38β Mitogen-activated Protein Kinase Possesses an Intrinsic Autophosphorylation Activity, Generated by a Short Region Composed of the α-G Helix and MAPK Insert

“…Furthermore, specific point mutations, D176A and F327(S‫گ‬L), also render p38␣ capable of autophosphorylation and autoactivation (13,14,20). p38␣ autophosphorylation has been shown to be physiologically relevant in the immune system (21,22) and in ischemic preconditioning (17,19) and to be sufficient to induce cellular senescence (23). The finding that MAPKs can autophosphorylate suggests that they are similar to most EPKs in this respect, but evolution provided them with inherent inhibition that prevents spontaneous autophosphorylation.…”

T cell priming: let there be light

“…Stimulation via the TCR leads to ZAP-70-dependent phosphorylation of p38 on Tyr-323, resulting in autophosphorylation of the activation loop of the kinase [4]. Studies using "knockin" mice in which p38α Tyr-323 was replaced with a Phe have shown that this alternative pathway is indispensable for TCR-induced, but not stress-induced, p38 activation in T cells, and in its absence there is a delay in the onset of proliferation and reduced IFN-γ expression [5]. von Essen et al found that p38 activation was actually enhanced in naïve compared to primed T cells and was inhibited (along with VDR upregulation) by inhibition of p38 kinase activity, a hallmark of the alternative p38 activation pathway because it prevents the necessary autophosphorylation step.…”