Trends in Molecular Medicine
ReviewNoncanonical NF-κB Signaling in Health and Disease
Section snippets
An Increased Understanding of Noncanonical NF-κB Signaling
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factors implicated in diverse biological processes, including inflammation, apoptosis, proliferation, and development (Box 1) 1, 2, 3. Based on the components of the signaling cascade, the NF-κB signaling pathway can be categorized as either a canonical or noncanonical pathway (Box 1).
The canonical NF-κB signaling pathway is regarded as the central regulator of the inflammatory response in normal
Core Elements of Noncanonical NF-κB Signaling
Noncanonical NF-κB signaling is regulated at multiple levels. Under normal conditions, NF-κB-inducing kinase (NIK) proteins are kept at low levels and, therefore, NIK stabilization is a critical step for the activation of the pathway (Figure 1 and Box 1) [4]. TNF receptor-associated factor 3 (TRAF3) acts as a crucial adaptor molecule for the regulation of NIK levels by controlling its proteasome-mediated degradation [4]. Although TRAF3 does not have enzymatic functions towards NIK, TRAF3–NIK
Novel Regulators of Noncanonical NF-κB Signaling
Recently, several important regulatory mechanisms and crosstalk interactions have been described for the noncanonical pathway. One important mechanism controlling NIK levels was proposed to involve the downstream target IKKα [13]. As a negative feedback mechanism after receptor activation, IKKα was found to phosphorylate NIK (on Ser 809, Ser 812, and Ser 815) for its destabilization, dampening signal transduction in various mouse and human cells [13]. Consistent with these results,
Mouse Models of Noncanonical NF-κB Signaling
The first genetic clues identifying the noncanonical NF-κB pathway came from the analysis of alymphoplasia (aly/aly) mice (see Glossary) 19, 20, 21. These mice harbor an amino acid substitution in the NIK protein acting downstream of CD40 and LTβR and interacting with several TRAF family members [22]. Importantly, the phenotypes associated with aly/aly mice have been shown to be more severe than in LTβR knockout (KO) mice. Whereas aly/aly mice present aberrantly low levels of B cells, LTβR KO
Noncanonical NF-κB Signaling in B Cell Development and Lymphoid Organogenesis
BAFF is an important factor for B cell survival and there are many transcriptional targets of BAFF signaling. For example, BAFF–NIK–p52 signaling was found to upregulate the antiapoptotic genes, Bcl-2 and Bcl-XL, which are essential for B cell survival [17], and repress apoptotic genes, such as Bim [44]. Recently, conditional KO studies have shed more light on the role of BAFF in B cell survival. Interestingly, apart from the noncanonical NF-κB pathway, BAFF has also been shown to activate PI3K
Noncanonical NF-κB Signaling in Cancer
The canonical NF-κB signaling pathway has been extensively studied in the context of cancer initiation, progression, and chemotherapy in both mice and humans 2, 75. However, the involvement of the noncanonical pathway in cancers is less well defined. The main mechanisms activating the noncanonical NF-κB pathway result from activation by viral oncogenes, mutations in pathway members, and upregulation of upstream components of the pathway 76, 77. In some cancer types, such as diffuse large B cell
Noncanonical NF-κB Signaling in Osteoclast Formation and Bone Disorders
RANKL and RANK are required for the formation of osteoclasts 31, 32. This phenotype is recapitulated in p52/p50 DKO mice, showing that both the canonical and noncanonical NF-κB signaling pathways are involved in osteoclast formation 33, 99. Using KO mouse models, p50/p52 have not been found to be required for the formation of RANK-expressing osteoclast progenitors, although they have been shown to be required for the differentiation of such progenitors into tartrate-resistant acid phosphatase
Therapeutic Options against the Noncanonical NF-κB Signaling Pathway
Given that aberrant activation of the noncanonical NF-κB signaling pathway is observed in various diseases, including cancers, bone disorders, and autoimmune diseases, targeting this pathway appears to be a viable therapeutic option. Several activators of this pathway can be specifically targeted. For example, TRAF3 degradation is mediated by proteasomal processing, and proteasomal inhibitors, such as bortezomib, carfilzomib, or NPI-0052, are currently being used in the treatment of many
Concluding Remarks
Noncanonical NF-κB signaling is important for various functions of immune cells and bone remodelling and it is aberrantly activated or repressed in many malignancies, autoimmune disorders, and bone disorders. When compared with the canonical NF-κB signaling pathway, much remains to be learned about the functional outcomes during the activation of this pathway. Consequently, information on noncanonical NF-κB signaling both in diseased and nondiseased contexts may generate novel therapeutic
Glossary
- Alymphoplasia (aly/aly) mice
- 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.
- Antibody class switching
- intrachromosomal deletional recombination process to generate antibody diversity in
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These authors contributed equally to this work.