Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:
9244310, PubMed:
9252186, PubMed:
9346484, PubMed:
18626576). Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues (PubMed:
9244310, PubMed:
9252186, PubMed:
9346484, PubMed:
18626576). These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome (PubMed:
9244310, PubMed:
9252186, PubMed:
9346484, PubMed:
18626576). In turn, free NF- kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis (PubMed:
9244310, PubMed:
9252186, PubMed:
9346484, PubMed:
18626576). Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11) (PubMed:
21765415). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes (PubMed:
20501937). In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF- kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities (PubMed:
17434128). Modulates chromatin accessibility at NF- kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP (PubMed:
12789342). Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro- apoptotic transcription factor (PubMed:
15084260). Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates AMBRA1 following mitophagy induction, promoting AMBRA1 interaction with ATG8 family proteins and its mitophagic activity (PubMed:
30217973).
