T cell receptor signals to NF-?B are transmitted by a cytosolic p62-Bcl10-Malt1-IKK signalosome.

ABSTRACT: Antigen-mediated stimulation of the T cell receptor (TCR) triggers activation of nuclear factor ?B (NF-?B), a key transcriptional regulator of T cell proliferation and effector cell differentiation. TCR signaling to NF-?B requires both the Carma1-Bcl10-Malt1 (CBM) complex and the inhibitor of ?B (I?B) kinase (IKK) complex; however, the molecular mechanisms connecting the CBM complex to activation of IKK are incompletely defined. We found that the active IKK complex is a component of a TCR-dependent cytosolic Bcl10-Malt1 signalosome containing the adaptor protein p62, which forms in effector T cells. Phosphorylated I?B? and NF-?B were transiently recruited to this signalosome before NF-?B translocated to the nucleus. Inhibiting the activity of the kinase TAK1 or IKK blocked the phosphorylation of IKK, but not the formation of p62-Bcl10-Malt1 clusters, suggesting that activation of IKK occurs after signalosome assembly. Furthermore, analysis of T cells from p62-deficient mice demonstrated that the p62-dependent clustering of signaling components stimulated activation of NF-?B in effector T cells. Thus, TCR-stimulated activation of NF-?B requires the assembly of cytosolic p62-Bcl10-Malt1-IKK signalosomes, which may ensure highly regulated activation of NF-?B in response to TCR engagement.

SUBMITTER: Paul S 

PROVIDER: S-EPMC6450650 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature