- The NF-κB (Nuclear Factor kappa B) pathway is a key mediator of inflammatory and immune responses, as well as cell survival and proliferation. The pathway exists in two main forms: the canonical and non-canonical pathways, both culminating in the activation of NF-κB transcription factors.
- In the canonical pathway, NF-κB dimers (typically p65/p50) are held inactive in the cytoplasm by IκB proteins. Upon stimulation by factors like TNF-α, IL-1, or LPS, the IKK complex (consisting of IKKα, IKKβ, and NEMO) becomes activated. The IKK complex then phosphorylates IκB, marking it for ubiquitination and proteasomal degradation. This releases NF-κB dimers to enter the nucleus.
- The non-canonical pathway, activated by specific stimuli like CD40L and BAFF, involves the processing of p100 to p52. This process depends on NIK (NF-κB-inducing kinase) and IKKα, but not NEMO. The resulting p52/RelB dimers then translocate to the nucleus.
- Once in the nucleus, NF-κB proteins bind to specific DNA sequences and regulate the expression of numerous genes involved in inflammation, immunity, cell survival, and proliferation. These include cytokines, chemokines, adhesion molecules, and anti-apoptotic factors.
- The pathway is regulated by multiple mechanisms including negative feedback loops (such as IκB synthesis), post-translational modifications of NF-κB proteins, and crosstalk with other signaling pathways. Dysregulation of NF-κB signaling is implicated in chronic inflammation, autoimmune diseases, and cancer, making it an important therapeutic target.
