The noncanonical NF‐κB pathway

Summary: The noncanonical nuclear factor‐κB (NF‐κB) signaling pathway mediates activation of the p52/RelB NF‐κB complex and, thereby, regulates specific immunological processes. This NF‐κB pathway relies on the inducible processing of NF‐κB2 precursor protein, p100, as opposed to the degradation of IκBα in the canonical NF‐κB pathway. A central signaling component of the noncanonical NF‐κB pathway is NF‐κB‐inducing kinase (NIK), which functions together with a downstream kinase, IKKα (inhibitor of NF‐κB kinase α), to induce phosphorylation‐dependent ubiquitination and processing of p100. Under normal conditions, NIK is targeted for continuous degradation by a tumor necrosis factor (TNF) receptor‐associated factor‐3 (TRAF3)‐dependent E3 ubiquitin ligase. In response to signals mediated by a subset of TNF receptor superfamily members, NIK becomes stabilized as a result of TRAF3 degradation, leading to the activation of noncanonical NF‐κB. This review discusses both the historical perspectives and the recent progress in the regulation and biological function of the noncanonical NF‐κB pathway.