NIK Signaling Functions Through Non-Canonical NF-κB Pathway and NF-κB-Independent Pathways (IMAGE)
Caption
NIK is the central regulator of the non-canonical NF-κB pathway, which is triggered by signaling from a subset of TNFR members. Upon receptor crosslinking by corresponding ligands, TRAFs and cIAP1/2 are recruited to the receptor, where cIAP1/2 ubiquitinates TRAF3 and leads to its degradation, resulting in the liberation and stabilization of NIK. Accumulated NIK activates IKKα, which in turn phosphorylates p100, leading to p100 processing and p52 generation. The NF-κB proteins p52 and RelB are then translocated to the nucleus and activate gene expression. Under certain conditions, NIK also induces degradation of p100/IkBδ, leading to activation of different NF-κB members. NIK also exerts NF-κB-independent functions, including mitochondrial fitness and metabolic functions. In T cells, activated NIK phosphorylates and promotes the function of a metabolic enzyme, G6PD, which catalyzes the generation of NADPH, thereby controlling cellular ROS and preventing autophagic degradation of HK2, a rate-limiting enzyme in glycolysis. At least in some cell types, NIK also promotes mitochondrial fission by facilitating mitochondrial recruitment and phosphorylation of the mitochondrial fission regulator Drp1. In hepatocytes, NIK phosphorylates JAK2 at serine 633, which interferes with phosphorylation of the adjacent tyrosine 637 required for JAK2 activation, thus inhibiting activation of the JAK2-STAT3/STAT5 signaling axis, and influencing cell cycle progression
Credit
Prof. Shao‑Cong Sun from Capital Institute for Medical Sciences Innovation, China Image source link: https://link.springer.com/article/10.1007/s44466-026-00026-4
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