An overview of NF-κB-independent functions of IKK subunits

IKK (IκB kinase) complex serves as the core component of the NF-κB signaling pathway. Its canonical function is to phosphorylate IκB proteins, thereby promoting the nuclear translocation and transcriptional activation of NF-κB. However, in recent years, it has been found that subunits of IKK complex (IKKα, IKKβ and IKKγ/NEMO) are widely involved in cell cycle regulation, autophagy, DNA damage repair, metabolic reprogramming and tumor metastasis independent of NF-κB pathway (defined as the function of IKK mediated through non classical or non-IκB substrates). This functional versatility is precisely governed by stimulus strength/duration, subcellular compartmentalization, scaffold protein usage, and differential substrate phosphorylation thresholds, which enable the same core kinase machinery to robustly control seemingly contradictory signaling outputs. In this paper, the nonclassical functions and molecular mechanisms of IKK subunits are systematically reviewed, which provides a new perspective for the targeted treatment of IKK related diseases.