TRAF trimers form immune signalling networks via RING domain dimerization

For many inflammatory cytokines the response elicited is dependent on the recruitment of the TNF receptor-associated factor (TRAF) family of adaptor proteins. All TRAF proteins have a trimeric C-terminal TRAF domain, while at the N-terminus most TRAFs have a RING domain that forms dimers. The symmetry mismatch of the N- and C-terminal halves of TRAF proteins means that when receptors cluster, it is presumed that RING dimers connect TRAF trimers to form a network. Here, using purified TRAF6 proteins, we provide direct evidence in support of this model, and we show that TRAF6 trimers bind Lys63-linked ubiquitin chains to promote their processive assembly. This study provides critical evidence in support of TRAF trimers as key players in signalling.