Activation of noncanonical NF-κB requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2, TRAF3 and the kinase NIK

Recent studies suggest that nuclear factor κB-inducing kinase (NIK) is suppressed through constitutive proteasome-mediated degradation regulated by TRAF2, TRAF3 and cIAP1 or cIAP2. Here, we demonstrated that the degradation of NIK occurred upon assembly of a regulatory complex through TRAF3 recruitment of NIK and TRAF2 recruitment of cIAP1 and cIAP2. In contrast to TRAF2 and TRAF3, cIAP1 and cIAP2 seem to play redundant roles in the degradation of NIK, as inhibition of both cIAPs was required for noncanonical NF-κB activation and increased survival and proliferation of primary B lymphocytes. Furthermore, the lethality of TRAF3-deficient mice could be rescued by a single NIK gene, highlighting the importance of tightly regulated NIK. The Rel-NF-κB family of transcription factors has a tremendous impact on numerous biological processes, including bone homeostasis, cellular proliferation and apoptosis, the initiation and propagation of innate and adaptive immune responses, and the development of secondary lymphoid tissue architecture1–3. Research in recent years has defined two distinct NF-κB activation pathways, termed the canonical and noncanonical NF-κB pathways4