NFKBID

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, delta also known as IκBNS is a protein in humans that is encoded by the NFKBID gene.[5]

NFKBID
Identifiers
Aliases	NFKBID, IkappaBNS, TA-NFKBH, NFKB inhibitor delta, IkBNS
External IDs	MGI: 3041243 HomoloGene: 13101 GeneCards: NFKBID
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.12 Start 35,887,653 bp[1] End 35,902,303 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 B1 Start 30,421,732 bp[2] End 30,428,746 bp[2]
Gene ontology Molecular function • GO:0001948 protein binding • GO:0001104 transcription coregulator activity • NF-kappaB binding Cellular component • cell nucleus Biological process • regulation of transcription from RNA polymerase II promoter • negative regulation of T cell differentiation in thymus • positive regulation of thymocyte apoptotic process • inflammatory response • negative regulation of NF-kappaB transcription factor activity • negative regulation of I-kappaB kinase/NF-kappaB signaling • T cell receptor signaling pathway • positive regulation of T-helper 17 cell differentiation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	84807	243910
Ensembl	ENSG00000167604	ENSMUSG00000036931
UniProt	Q8NI38	Q2TB02
RefSeq (mRNA)	NM_139239 NM_001321831 NM_001365705 NM_001365706 NM_032721	NM_172142 NM_001360906 NM_001360907
RefSeq (protein)	NP_001308760 NP_640332 NP_001352634 NP_001352635 NP_116110	NP_742154 NP_001347835 NP_001347836
Location (UCSC)	Chr 19: 35.89 – 35.9 Mb	Chr 7: 30.42 – 30.43 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

IκBNS is a member of the atypical inhibitors of NF-κB (also called the nuclear IκBs). NF-κB is a transcription factor, which regulates the expression of its target genes, depending on intracellular and extracellular signals. As NFKBID influences the impact of NF-κB on several genes, it is involved in cellular responses to stimuli such as stress and bacterial or viral antigens.

Structure

NFKBID is a nuclear protein with 327 amino acids. It contains six ankyrin repeats (ANKs), that are surrounded by a nuclear localization signal sequence (NLS) at the N-terminus and a short C-terminus.[6][7] The ANKs are characteristic for all IκB proteins. The NLS is an additional characteristic structural element of only atypical IκB proteins, which is responsible for the localization of the protein into the nucleus. In contrast, classical inhibitors, e.g. IκBα and IκBβ, are located in the cytoplasm. A high resolution structure of NFKBID is not available yet.

Scheme of NFKBID. It consists of six ankyrin domains (ANK – blue) and a nuclear localization signal sequence (NLS – green).

Function

It seems that NFKBID acts as an inhibitor of the NF-κB cascade. By its functions, including promotion of germinal center reactions and its requirement in imunosuppressive regulatory T cell generation, NFKBID regulates homeostasis of the immune system and has further different consequences on it.[6] Furthermore, NFKBID influences B cells and plasma cells substantially, concerning their functions and development.[8]

The expression of NFKBID is precisely regulated. After NF-κB activation atypical IκBs are induced by the transcription factor [7] Atypical IκBs, in turn, can regulate the NF-κB transcription as either inducers or inhibitors. In contrast, the classical proteins can only repress NF-κB transcription.[6] In mature T cells (CD4+), T cell receptor (TCR) stimulation can induce the expression of NFKBID, whereas in macrophages, TLR ligands take on this task.[9][10]

To influence the transcription of genes, NFKBID has some interaction protein partners. It was reported that NFKBID interacts with p50, which is a subunit of NF-κB, p52, p65, RelB, and c-Rel. NFKBID binds these proteins only in the nucleus, except for p50, which can be bound both in the cytoplasm and in the nucleus [11][12] Researchers suggest that apart from this, NFKBID can also interact with homo- and heterodimers consisting of some of these subunits, e.g. p50/p50 and p65/p50.[13] Depending on the target gene and on which protein is bound by NFKBID, it can function as both repressor and activator.

Interaction model of NFKBID (purple) with the p50 homodimer (green and blue) bound to DNA (red). The complex was studied by molecular docking experiments. The NFKBID-p50/p50 complex interacts electrostatically with phosphates of the DNA backbone. Therefore, the protein complex is not able to exit the nucleus. The mainly positively charged surface of NFKBID close to DNA blocks the exchange of the p50/p50 dimer with other dimers, that are activating transcription factors.[13]

References

1. GRCh38: Ensembl release 89: ENSG00000167604 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000036931 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, delta".
6. Schuster M, Annemann M, Plaza-Sirvent C, Schmitz I (2013). "Atypical IκB proteins - nuclear modulators of NF-κB signaling". Cell Commun Signal. 11 (1): 23. doi:10.1186/1478-811X-11-23. PMC 3639191. PMID 23578005.
7. Chiba T, Inoko H, Kimura M, Sato T (2013). "Role of nuclear IκBs in inflammation regulation". Biomol Concepts. 4 (2): 187–96. doi:10.1515/bmc-2012-0039. PMID 25436575. S2CID 4544736.
8. Touma M, Keskin DB, Shiroki F, Saito I, Koyasu S, Reinherz EL, Clayton LK (2011). "Impaired B cell development and function in the absence of IkappaBNS". J. Immunol. 187 (8): 3942–52. doi:10.4049/jimmunol.1002109. PMC 3348541. PMID 21900180.
9. Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Pfeffer K, Huehn J, Siegmund B, Schmitz I (2012). "IκB(NS) protein mediates regulatory T cell development via induction of the Foxp3 transcription factor". Immunity. 37 (6): 998–1008. doi:10.1016/j.immuni.2012.08.023. PMID 23200824.
10. Kuwata H, Matsumoto M, Atarashi K, Morishita H, Hirotani T, Koga R, Takeda K (2006). "IkappaBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation". Immunity. 24 (1): 41–51. doi:10.1016/j.immuni.2005.11.004. PMID 16413922.
11. Hirotani T, Lee PY, Kuwata H, Yamamoto M, Matsumoto M, Kawase I, Akira S, Takeda K (2005). "The nuclear IkappaB protein IkappaBNS selectively inhibits lipopolysaccharide-induced IL-6 production in macrophages of the colonic lamina propria". J. Immunol. 174 (6): 3650–7. doi:10.4049/jimmunol.174.6.3650. PMID 15749903.
12. Fiorini E, Schmitz I, Marissen WE, Osborn SL, Touma M, Sasada T, Reche PA, Tibaldi EV, Hussey RE, Kruisbeek AM, Reinherz EL, Clayton LK (2002). "Peptide-induced negative selection of thymocytes activates transcription of an NF-kappa B inhibitor". Mol. Cell. 9 (3): 637–48. doi:10.1016/s1097-2765(02)00469-0. PMID 11931770.
13. Manavalan B, Basith S, Choi YM, Lee G, Choi S (2010). "Structure-function relationship of cytoplasmic and nuclear IκB proteins: an in silico analysis". PLOS ONE. 5 (12): e15782. doi:10.1371/journal.pone.0015782. PMC 3009747. PMID 21203422.