CHUK
Description
The CHUK (component of inhibitor of nuclear factor kappa B kinase complex) is a protein-coding gene located on chromosome 10.
Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the CHUK gene. IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor. However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.
== Function ==
=== NF-κB response ===
IKK-α is a member of the serine/threonine protein kinase family and forms a complex in the cell with IKK-β and NEMO. NF-κB transcription factors are normally held in an inactive state by the inhibitory proteins IκBs. IKK-α and IKK-β phosphorylate the IκB proteins, marking them for degradation via ubiquitination and allowing NF-κB transcription factors to go into the nucleus. Once activated, NF-κB transcription factors regulate genes that are implicated in many important cellular processes, including immune response, inflammation, cell death, and cell proliferation.
=== Epidermal differentiation === IKK-α has been shown to function in epidermal differentiation independently of the NF-κB pathway. In the mouse, IKK-α is required for cell cycle exit and differentiation of the embryonic keratinocytes. IKK-α null mice have a truncated snout and limbs, shiny skin, and die shortly after birth due to dehydration. Their epidermis retains a proliferative precursor cell population and lacks the outer two most differentiated cell layers.
CHUK, also known as IKK-α, is a serine kinase that plays a crucial role in the NF-κB signaling pathway. This pathway is activated by various stimuli such as inflammatory cytokines, bacterial or viral products, DNA damage, or other cellular stresses. CHUK acts as a part of the canonical IKK complex in the conventional NF-κB activation pathway, where it phosphorylates inhibitors of NF-κB on serine residues. This phosphorylation leads to the polyubiquitination and subsequent degradation of the inhibitors by the proteasome. Consequently, free NF-κB translocates to the nucleus and activates the transcription of hundreds of genes involved in immune responses, growth control, and protection against apoptosis. CHUK also negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1, thereby promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex. This complex contributes to limiting inflammatory gene activation by providing a negative feedback loop. In the non-canonical NF-κB activation pathway, MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52. This leads to the formation of NF-κB RelB-p52 complexes, which regulate genes involved in B-cell survival and lymphoid organogenesis. CHUK also participates in the negative feedback of the non-canonical NF-κB signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Furthermore, CHUK interacts with CREBBP within the nucleus, enhancing both its transcriptional and histone acetyltransferase activities. This interaction modulates chromatin accessibility at NF-κB-responsive promoters by phosphorylating histones H3 at 'Ser-10', which are subsequently acetylated at 'Lys-14' by CREBBP. CHUK also phosphorylates the CREBBP-interacting protein NCOA3. CHUK may regulate the pro-apoptotic transcription factor FOXO3 by phosphorylating it. It also phosphorylates RIPK1 at 'Ser-25', repressing its kinase activity and preventing TNF-mediated RIPK1-dependent cell death. Following mitophagy induction, CHUK phosphorylates AMBRA1, promoting its interaction with ATG8 family proteins and enhancing its mitophagic activity. CHUK is a component of the I-κB-kinase (IKK) core complex, which consists of CHUK, IKBKB, and IKBKG. The core complex likely associates with regulatory or adapter proteins to form an IKK-signalosome holo-complex. This complex can interact with TERF2IP/RAP1, promoting IKK-mediated phosphorylation of RELA/p65. CHUK is also part of a complex containing NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG, and CREBBP. Additionally, it is part of a 70-90 kDa complex consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1, and MAP3K14. CHUK directly interacts with TRPC4AP and may interact with TRAF2, NALP2, MAVS/IPS1, ARRB1, ARRB2, NLRC5, PIAS1, ZNF268 isoform 2, FOXO3, IFIT5, LRRC14, SASH1, and DDX3X. CHUK also interacts with InlC of Listeria monocytogenes.
CHUK is also known as BPS2, IKBKA, IKK-1, IKK-alpha, IKK1, IKKA, NFKBIKA, TCF16.
