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Pathway Description
Noncanonical NF-κB Signaling
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Signaling
Created: 2025-04-20
Last Updated: 2025-04-21
Activation of the non‑canonical NF‑κB pathway is initiated by engagement of specific TNF superfamily receptors (BAFF‑R, CD40, LTβR, RANK), which upon ligand binding recruit a TRAF3–TRAF2–cIAP1/2 E3 ubiquitin–ligase complex that targets TRAF3 for proteasomal degradation, thus rescuing NF‑κB–inducing kinase (NIK) from its constitutive turnover and allowing NIK to accumulate. Accumulated NIK phosphorylates and activates the IKKα homodimer, which in turn phosphorylates the p100 precursor on key serine residues, eliciting its partial processing by the β‑TrCP ubiquitin ligase into p52. The resulting RelB/p52 heterodimers translocate to the nucleus where they drive transcription of genes essential for secondary and tertiary lymphoid organogenesis, B‑cell maturation and class‑switch recombination, and thymic epithelial cell development for T‑cell central tolerance. This pathway operates with slow kinetics yet sustained activity, fitting its developmental and homeostatic roles, and is subject to tight negative feedback via IKKα‑mediated NIK degradation and OTUD7B‑mediated deubiquitination of TRAF3, restoring the steady‑state balance. Genetic defects in this cascade, such as mutations in NIK or the NF‑κB2 precursor p100, lead to immunodeficiency characterized by hypogammaglobulinemia and impaired lymphoid tissue formation, whereas aberrant activation is implicated in chronic inflammatory diseases and certain lymphoid malignancies, underscoring the pathway’s critical importance and therapeutic potential.
References
Noncanonical NF-κB Signaling References
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