Alt. symbols: TCF16 | IKK1 | IKK-alpha | IkBKA | NFKBIKA | IKKA

Approved name: component of inhibitor of nuclear factor kappa B kinase complex
Alt. names: conserved helix-loop-helix ubiquitous kinase | inhibitor of nuclear factor kappa-B kinase subunit alpha, I-kappa-B kinase

Location: 10q24.31: 100188300 - 100229596 (-)
Gene type: protein_coding, 4 transcripts.

Scores: LoFtool: 0.345000 | pLI: 0.99870371 | LOEUF: 0.285

HGNC: 1974

NCBI: 1147, RefSeq: NG_028023.1

Ensembl: ENSG00000213341.11

LRG_ | Status: none

OMIM: 600664

Expression | ProteinAtlas

CHUK encodes a Ser/Thr kinase that functions in both canonical and non-canonical NF-κB signaling. As part of the canonical pathway, it is a member of the IKK complex. Its phosphorylation of IKKβ leads to polyubiquitination and subsequent degradation by the proteasome, enabling free NF-kB to translocate into the nucleus and activate the transcription. It also provides negative feedback on this pathway by phosphorylating the scaffold protein TAXBP1 to promote assembly of the A20 ubiquitin-editing complex. As part of the non-canonical pathway, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of RelB-p52 complexes, which then regulate B-cell survival and lymphoid organogenesis transcriptional programs. Similar to above, it also provides negative feedback on this pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, CHUK modulates chromatin accessibility at NF-kB-responsive promoters by phosphorylating H3 at S10 (with subsequently acetylation at K14 by CREBBP) as well as phosphorylating CREBBP directly to increase both its transcriptional and histone acetyltransferase activities. Other substrates include CREBBP-interacting protein NCOA3, FOXO3, RIPK1 (repressing its kinase activity and preventing TNF-mediated RIPK1-dependent cell death), and AMBRA1 (promoting its interaction with ATG8 family proteins and mitophagy).

Using a combined strategy of gene-expression arrays, candidate-gene analysis, clinical studies, and genealogic investigations, Lahtela et al. (2010) first described a homozygous CHUK missense mutation in a Finnish family with multiple congenital anomalies leading to pregnancy loss, with the most obvious anomalies being craniofacial dysmorphism and seemingly absent limbs, which are bound to the trunk and encased under the skin, leading to the designation of Cocoon syndrome [MIM:613630] (PMID: 209 61246). Riller et al. (2024) identified compound heterozygous CHUK variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features (PMID: 38798321). This patient had almost no circulating B cells or plasmablasts and a high proportion of naive CD4+ and CD8+ T cells along with low NK, MAITs cells. Moreover, she had neutralizing autoantibodies against type I IFN, which is seen in other non-canonical NF-κB pathway deficiencies. The authors showed that both IKKα variants led to kinase loss-of-function with near-absent non-canonical NF-κB activation in stromal and immune cells and partially impaired canonical pathway activation. Lentiviral transduction of wild-type CHUK rescued non-canonical NF-κB activation in fibroblasts. [Load More]