T Cell Receptor Signals to NF-κB 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 κB (NF-κB), a key transcriptional regulator of T cell proliferation and effector cell differentiation. TCR signaling to NF-κB requires both the Carma1-Bcl10-Malt1 (CBM) complex and the inhibitor of κB (IκB) 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 IκBα and NF-κB were transiently recruited to this signalosome before NF-κB 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-κB in effector T cells. Thus, TCR-stimulated activation of NF-κB requires the assembly of cytosolic p62-Bcl10-Malt1-IKK signalosomes, which may ensure highly regulated activation of NF-κB in response to TCR engagement.

Gain-of-function mutations and immunodeficiency

“…In lymphocytes, AgR ligation triggers the phosphorylation of an inhibitory “linker” domain in CARD11 that normally maintains the protein in a closed, inactive conformation (11, 12). Linker phosphorylation “opens” the CARD11 molecule to recruit BCL10 and MALT1, which nucleates the formation of dynamic multi-protein signalosomes responsible for activating inhibitor of κB kinase (IKK) (13–15). IKK-mediated phosphorylation marks the inhibitor of κB (IκB) for ubiquitination and proteosomal degradation, thereby facilitating the nuclear translocation of NF-κB for gene transcription.…”

Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

“…It has been shown, that MALT1 recruits the E3 ligase TRAF6 through its TRAF6 binding motifs inducing TRAF6 oligomerization and activation, which results in the conjugation of polyubiquitin chains to MALT1 and NEMO (Oeckinghaus et al, 2007;Shambharkar et al, 2007). TRAF6 further interacts with the ubiquitin adapter protein p62, which recognizes polyubiquitinated BCL10-MALT1 molecules forcing the formation of large cytosolic p62-BCL10-MALT1 signaling clusters, which also recruit the IKK complex and thus provide a compartment to enhance downstream signaling (Paul et al, 2014). Of note, IKK activation was suggested to be driven by a dual process involving CBM and TRAF6 dependent NEMO ubiquitination and PKCθ-TAK1 catalyzed IKKβ phosphorylation, the latter independent of CBM assembly ( Shambharkar et al, 2007).…”

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

“…The ubiquitinated Bcl10 binds to preexisting p62 aggregates, leading to the formation of POLKADOTS. The POLKADOTS seem to be dispensable for IKK/NF-κB activation in naïve T cells, but they do play a role in IKK/NF-κB activation in effector T cells (Paul et al, 2014). The POLKADOTS appear to provide a compartment, in which activated IKK interacts with and phosphorylates its substrate IκBα.…”

“…In addition, NF-κB members, particularly RelA, are also transiently recruited to the POLKADOTS upon TCR crosslinking. Genetic ablation of p62 reduces the formation of POLKADOTS and activation of IKK in effector T cells (Paul et al, 2014). These findings are consistent with the earlier observations that p62 is important for IKK/NF-κB activation in Th2 effector T cells but not in naïve T cells (Martin et al, 2006).…”

“…These findings are consistent with the earlier observations that p62 is important for IKK/NF-κB activation in Th2 effector T cells but not in naïve T cells (Martin et al, 2006). It is thought that the differential roles of p62 in regulating NF-κB signaling in naïve versus effector T cells are due to the low levels of p62 expression in naïve T cells (Paul et al, 2014; Yang et al, 2010). The specific requirement of POLKADOTS signalosome for NF-κB signaling in effector T cells is intriguing, although the precise mechanism of its action requires additional studies.…”