Distinct sites in ADAP control IKKα/β phosphorylation, IKKγ ubiquitination and cell cycle progression in T cells. (50.43)

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Abstract NF-κB activation following TCR engagement involves PKCθ-dependent assembly of the CARMA1-BCL10-MALT1 (CBM) signalosome, which coordinates downstream activation of IκB-kinase (IKK). We previously identified a novel role for the adhesion and degranulation-promoting adapter protein (ADAP) in regulating the assembly of the CBM complex via an interaction of ADAP with CARMA1. The ADAP interacts with another adaptor protein SKAP55 which is critical for for T cell integrin activation and T:APC conjugate formation. In this study, we identify a novel site in ADAP that is critical for association with the TGFβ activated kinase (TAK1). ADAP is critical for recruitment of TAK1 and the CBM complex, but not IKK, to PKCθ. While both the TAK1 and CARMA1 binding sites in ADAP are essential for IκB phosphorylation and degradation, only the TAK1 binding site in ADAP is necessary for IKK phosphorylation. In contrast, only the CARMA1 binding site in ADAP is required for ubiquitination of IKKγ. Loss of ADAP in ADAP-/- primary T cells led to a block in G1-S transition. Expression of ADAP mutants lacking TAK1 and CARMA1 binding sites do not rescue the block in cell cycle progression while ADAP mutant lacking the SKAP55 binding site rescued cell cycle progression. Thus, distinct sites within ADAP control two key activation responses that are required for NF-κB activation and provide unique signals for cell cycle cycle progression and T cell poliferation.