Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG-I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Phosphorylates AKT1. ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L-seryl-[I-kappa-B protein] Homodimer. Interacts with MAVS/IPS1 (PubMed:16177806, PubMed:28011935, PubMed:27980081). Interacts (via protein kinase domain) with TTLL12 (via N-terminus); the interaction prevents MAVS binding to IKBKE (PubMed:28011935). Interacts with the adapter proteins AZI2/NAP1, TANK and TBKBP1/SINTBAD (PubMed:17568778). Interacts with SIKE1 (PubMed:16281057, PubMed:14560022). Interacts with TICAM1/TRIF, IRF3 and DDX58/RIG-I; interactions are disrupted by the interaction between IKBKE and SIKE1 (PubMed:14739303, PubMed:16281057, PubMed:23478265). Interacts with TOPORS; induced by DNA damage (PubMed:20188669). Interacts with CYLD (PubMed:18636086). Interacts (when polyubiquitinated) with IKBKB, IKBKG and MYD88 (PubMed:23453969). Interacts with IFIH1 (PubMed:17600090). Interacts with DDX3X; the interaction may be induced upon virus infection (PubMed:18636090, PubMed:20657822, PubMed:23478265, PubMed:27980081). Interacts with TRIM6 (via SPRY box) (PubMed:24882218). Interacts with unanchored K48-linked polyubiquitin chains; this leads to IKBKE activation (PubMed:24882218). Interacts with TBK1 (PubMed:29251827). Interacts with FKBP5 (PubMed:26101251, PubMed:31434731). (Microbial infection) Interacts (via Protein kinase domain) with arenavirus protein N; the interaction inhibits IKBKE kinase function. (Microbial infection) Interacts with Ebola virus protein VP35; the interaction leads to inhibition of cellular antiviral response by blocking necessary interactions between the IKBKE and MAVS/IPS as well as its substrates IRF3 and IRF7. (Microbial infection) Interacts with Severe fever with thrombocytopenia virus (SFTSV) NSs; this interaction this interaction sequesters IKBKE in NSs-induced cytoplasmic inclusion bodies thereby inhibiting the IFN responses. (Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein HBZ. Targeting to PML nuclear bodies upon DNA damage is TOPORS-dependent (PubMed:20188669). Located diffusely throughout the cytoplasm but locates to punctate cytoplasmic bodies when coexpressed with TRIM6 (PubMed:24882218). Highly expressed in spleen followed by thymus, peripheral blood leukocytes, pancreas, placenta. Weakly expressed in lung, kidney, prostate, ovary and colon. Induced by lipopolysaccharide (LPS) and TNFA. Autophosphorylated and phosphorylated by IKBKB/IKKB. Phosphorylation at Ser-172 is enhanced by the interaction with DDX3X. Phosphorylated at Thr-501 upon IFN activation. Sumoylation by TOPORS upon DNA damage is required for protection of cells against DNA damage-induced cell death. Desumoylated by SENP1. 'Lys-63'-linked polyubiquitinated at Lys-30 and Lys-401 by TRAF2:BIRC2 and TRAF2:BIRC3 complexes. Ubiquitination is induced by LPS, TNFA and interleukin-1 and required for full kinase activity and KF-kappa-B pathway activation. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. Extended N-terminus.