Targeting signaling factors for degradation, an emerging mechanism for TRAF functions

Summary Tumor necrosis factor receptor ( TNFR )‐associated factors ( TRAF s) form a family of proteins that are best known as signaling adapters of TNFR s. However, emerging evidence suggests that TRAF proteins, particularly TRAF 2 and TRAF 3, also regulate signal transduction by controlling the fate of intracellular signaling factors. A well‐recognized function of TRAF 2 and TRAF 3 in this aspect is to mediate ubiquitin‐dependent degradation of nuclear factor‐κB ( NF ‐κB)‐inducing kinase ( NIK ), an action required for the control of NIK ‐regulated non‐canonical NF ‐κB signaling pathway. TRAF 2 and TRAF 3 form a complex with the E3 ubiquitin ligase cIAP ( cIAP 1 or cIAP 2), in which TRAF 3 serves as the NIK ‐binding adapter. Recent evidence suggests that the cIAP ‐ TRAF 2‐ TRAF 3 E3 complex also targets additional signaling factors for ubiquitin‐dependent degradation, thereby regulating important aspects of immune and inflammatory responses. This review provides both historical aspects and new insights into the signaling functions of this ubiquitination system.