Noncanonical NF-κB Signaling in Health and Disease

Under 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. 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. 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. mice that lack lymph nodes and Peyer's patches, have defective splenic and thymic architecture, and impaired antibody responses. These phenotypes are caused by a naturally occurring point mutation in the murine Nik gene resulting in a G855R amino acid substitution in the mouse NIK protein. This mutation disrupts the interaction between NIK and IKKα proteins. intrachromosomal deletional recombination process to generate antibody diversity in mature B cells mediated by antigen stimulation and co-stimulatory signals. a member of the TNF ligand superfamily (TNFSF), also known as TNFSF13B. It is important for B cell survival. reside in B cell follicles of spleen and lymph nodes and represent >95% of B cells in peripheral lymph nodes. a distinct subset of CD4+ helper T (Th) cells that regulate the development of antigen-specific B cell immunity. Upon exposure to a foreign antigen, Tfh cells help B cells generate antibody-producing plasma cells and long-lived memory B cells a small subset of T cells expressing T cell receptor (TCR) chain heterodimers from gamma and delta gene loci; important in mucosal immunity. sites found in secondary lymphoid organs, such as spleen and lymph node. They are important for the generation of B cell diversity and antigen class switching. enzyme catalyzing the first step of tryptophan catabolism. It acts as an immunosuppressive enzyme in dendritic cells. a member of the TNF ligand superfamily (TNFSF), also known as TNFSF14. Secreted from cells and acts as a ligand for TNFRSF14. LIGHT mediates different functions, acting as a co-stimulatory factor for lymphoid cells and stimulating T cell proliferation. a member of the TNFSF. Forms heterotrimer complex with LTα on the cell surface, mainly in the form of LTα1β2, and signals through the LTβ receptor (LTβR) expressed on target cells. reside in the marginal zone of spleens and are phenotypically distinguishable from follicular B cells. a bone disease rendering bones unusually dense and brittle. small aggregates of lymphatic tissue in the lowest part of the small intestine; involved in immune surveillance in intestinal lumen and mucosal immunity. a subset of T cells essential for suppressing immune responses. Their dysfunction is intimately involved in autoimmune disorders. a subset of Th cells producing mainly interferon gamma (IFNγ) and IL2. They are important for host defense against intracellular microbes and viruses. a subset of Th cells producing IL17. They are particularly important for tissue homeostasis against extracellular pathogens.