Noncanonical NF-κB Signaling in Health and Disease

Noncanonical NF-κB signaling differs from canonical NF-κB signaling by being activated through different cell surface receptors, cytoplasmic adaptors, and NF-κB dimers. Under normal physiological conditions, this noncanonical pathway has been implicated in diverse biological processes, including lymphoid organogenesis, B cell maturation, osteoclast differentiation, and various functions of other immune cells. Recently, dysfunction of this pathway has also been causally associated with numerous immune-mediated pathologies and human malignancies. Here, we summarize the core elements as well as the recently identified novel regulators of the noncanonical NF-κB signaling pathway. The involvement of this pathway in different pathologies and the potential therapeutic options that are currently envisaged are also discussed.

TrendsUnder normal physiological conditions, noncanonical Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling is mainly involved in lymphoid organogenesis as well as B cell survival and maintenance. Lymphotoxin beta receptor (LTβR) signaling in endothelial cells is also essential for peripheral lymph node formation and lymphocyte homing.Aberrant activation of this pathway is commonly observed in human malignancies, including multiple myeloma and diffuse large B cell lymphomas (DLBCL). In particular, TNF receptor-associated factor 3 (TRAF3) mutations and/or deletions are observed in 15% of patients with DLBCL.NF-κB-inducing kinase (NIK) is an important kinase of this pathway and is regulated post-translationally. NIK protein levels are critically regulated by a protein complex comprising TRAF3, TRAF2, and cellular inhibitor of apoptosis 1 and 2 (cIAP1/2). As a negative regulatory mechanism, NIK can also be phosphorylated by IKKα or TANK-Binding Kinase 1 (TBK1), and degraded to limit the activation of the pathway under different conditions.Therapeutically targeting NIK activity is a promising approach to treat diseases in which this pathway is constitutively activated.Recently, the noncanonical NF-κB signaling pathway has been implicated in metabolic diseases, contributing to disease progression.