USP2a positively regulates TCR-induced NF-κB activation by bridging MALT1-TRAF6

The paracaspase MALT1 is essential for the activation of NF-κB in response to T cell receptor(TCR)stimula-tion.It recruits downstream TRAF6 and activates the E3 ligase activity of TRAF6 to polyubiquitinate several targets,which ultimately leads to NF-κB activation.Here we identified ubiquitin-specific protease 2a(USP2a)as a MALT1-associated protein by biochemical affinity purification.Endogenous USP2a constitutively interacted with TRAF6,but dynamically interacted with MALT1 and CARMA1 in a stimulation-dependent man-ner.RNA interference(RNAi)-mediated silencing of USP2a attenuated TCR-induced NF-κB activation and production of interleukin-2(IL-2).In addition,the ubiq-uitination of MALT1 and TRAF6 were both suppressed by USP2a knockdown.By knockdown and reconstitu-tion assays,we found that USP2a mediated the interac-tion between MALT1 and TRAF6 in a catalytic activ-ity-dependent manner.Furthermore,USP2a deSUMOy-lated TRAF6.Our findings implicate that USP2a plays an important role in TCR signaling by deSUMOylating TRAF6 and mediating TRAF6-MALT1 interaction.