TCR signaling to NF-κB and mTORC1: Expanding roles of the CARMA1 complex

Abstract

Naïve T-cell activation requires signals from both the T-cell receptor (TCR) and the costimulatory molecule CD28. A central mediator of the TCR and CD28 signals is the scaffold protein CARMA1, which functions by forming a complex with partner proteins, Bcl10 and MALT1. A well-known function of the CARMA1 signaling complex is to mediate activation of IκB kinase (IKK) and its target transcription factor NF-κB, thereby promoting T-cell activation and survival. Recent evidence suggests that CARMA1 also mediates TCR/CD28-stimulated activation of the IKK-related kinase TBK1, which plays a role in regulating the homeostasis and migration of T cells. Moreover, the CARMA1 complex connects the TCR/CD28 signals to the activation of mTORC1, a metabolic kinase regulating various aspects of T-cell functions. This review will discuss the mechanism underlying the activation of the CARMA1-dependent signaling pathways and their roles in regulating T-cell functions.

Cell intrinsic role of NF-κB-inducing kinase in regulating T cell-mediated immune and autoimmune responses

“…We have previously shown that NIK is required for the induction of noncanonical NF-κB activation in T cells by the TCR and CD28 signals 29 . NIK also mediates T cell costimulation by OX40 and likely additional members of the TNFR family of costimulatory molecules cell subsets 11 30 . Thus, NIK may regulate T cell homeostasis via signaling pathways from both the TCR and TNFRs.…”

Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease

“…CARD11 also affects TCR-induced mechanistic target of rapamycin complex 1 (mTORC1) activation. 30,31 Therefore we further tested whether selected CARD11 variants could disrupt TCR-induced mTORC1 activation by measuring ribosomal S6 protein phosphorylation using immunoblotting. For most mutations within the CARD domain, we observed a trend toward decreased phospho-S6 levels (Fig 1, C and D), similar to those seen in previously characterized DN mutants.…”

p62/SQSTM1 functions as a signaling hub and an autophagy adaptor

“…In the present review, we focus on the emerging roles of p62 in mTORC1 activation, the Keap1-Nrf2 pathway, and selective autophagy. Functions of p62/Sqstm1 not covered in this review are discussed elsewhere [1][2][3][4][5]11].…”