Inhibition of nf-kb signaling by a20 through disruption of ubiquitin enzyme complexes

A20 negatively regulates inflammation by inhibiting the nuclear factor kB (NF-kB) transcription factor in the tumor necrosis factor receptor (TNFR) and Toll-like receptor (TLR) pathways. A20 contains deubiquitinase and E3 ligase domains and thus has been proposed to function as a ubiquitin-editing enzyme downstream of TNFRl by inactivating ubiquitinated RIP1. However, it remains unclear how A20 terminates NF-kB signaling downstream of TLRs. We have shown that A20 inhibited the E3 ligase activities of TRAF6, TRAF2, and clAPl by antagonizing interactions with the E2 ubiquitin conjugating enzymes Ubd3 and UbcH5c. A20, together with the regulatory molecule TAXlBPl, interacted with Ubc13 and UbcH5c and triggered their ubiquitination and proteasome-dependent degradation. These findings suggest a mechanism of A20 action in the inhibition of inflammatory signaling pathways.