Top ▲
Target has curated data in GtoImmuPdb
Target id: 3008
Nomenclature: NFKB inhibitor zeta
Abbreviated Name: IκBζ
Gene and Protein Information | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | - | 718 | 3q12.3 | NFKBIZ | NFKB inhibitor zeta | 8 |
Mouse | - | 728 | 16 C1.1 | Nfkbiz | nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, zeta | |
Rat | - | 379 | 11q12 | Nfkbiz | NFKB inhibitor zeta | |
Gene and Protein Information Comments | ||||||
Two transcripts from the human gene are reported. The first produces protein isoform a (718 aa) and the second encodes isoform b (618 aa). Similarly the mouse gene produces two protein isoforms; a (728 aa) and b (629 aa). |
Database Links | |
Alphafold | Q9BYH8 (Hs), Q9EST8 (Mm) |
Ensembl Gene | ENSG00000144802 (Hs), ENSMUSG00000035356 (Mm), ENSRNOG00000031163 (Rn) |
Entrez Gene | 64332 (Hs), 80859 (Mm), 304005 (Rn) |
Human Protein Atlas | ENSG00000144802 (Hs) |
KEGG Gene | hsa:64332 (Hs), mmu:80859 (Mm), rno:304005 (Rn) |
OMIM | 608004 (Hs) |
Pharos | Q9BYH8 (Hs) |
RefSeq Nucleotide | NM_031419 (Hs), NM_001005474 (Hs), NM_001159395 (Mm), NM_030612 (Mm), NM_001107095 (Rn) |
RefSeq Protein | NP_001005474 (Hs), NP_113607 (Hs), NP_001152867 (Mm), NP_085115 (Mm), NP_001100565 (Rn) |
UniProtKB | Q9BYH8 (Hs), Q9EST8 (Mm) |
Wikipedia | NFKBIZ (Hs) |
Immunopharmacology Comments |
IκBζ is a key component of the immune response that regulates the transcription of a set of inflamatory genes through its association with the p50 or p52 subunits of NF-κB. IκBζ acts as an inhibitor of primary NF-κB response genes, but may also act as a coactivator of the expression of secondary response genes (through association with the NF-κB p50 subunit). IκBζ is in fact the product of a primary NF-κB reponse gene, being rapidly upregulated by various inflammatory stimuli. Pro-inflammatory gene products that are regulated by IκBζ include CCL2, IL-6, IL12p40, IL-17, IFNγ, and GM-CSF [4-5]. In contrast, IκBζ acts as a transcriptional activator of anti-inflammatory IL-10 in macrophages [3]. In pathological conditions, IκBζ has been identified as a key driver of IL-17A-driven effects and TH17 cells in the development of psoriasis [4,7]. The itaconate (a marker of macrophage activation and metabolic switching) derivative dimethyl itaconate has been shown to ameliorate IκBζ-IL-17-driven psoriatic pathology in mice, indicating that this axis may be a novel pharmacological target for the treatment of psoriasis and other IκBζ-mediated autoimmune conditions [1]. |
Immuno Process Associations | ||
|
||
|
||
|
||
|
||
|
||
|
||
|
General Comments |
IκBζ is an atypical member of the IκB protein family, that like Bcl3 and IκBNS resides in the nucleus. IκBζ is involved in regulation of NF-κB transcription factor complexes, principally as an inhibitor of NF-κB transcriptional activity. IκBζ inhibits NF-κB inside the nucleus and does not affect NF-κB nuclear translocation. It is ubiquitously expressed at low levels in resting cells. Expression is upregulated in response to Toll-like/IL-1 receptor activation through an IRAK1/IRAK4/NF-κB-dependent pathway. IκBζ's primary biological function is in innate immunity, but a role for IκBζ in adaptative immunity cannot be discounted. As an important regulator of inflammation, cell proliferation and survival IκBζ may have a role to play in cancer pathogenesis [9], particulary in light of evidence that elevated IκBζ expression has been detected in lymphoid cancer models [6] and primary testicular and central nervous system lymphomas [2]. |
1. Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, Korenfeld D, Mathyer ME, Kim H, Huang LH et al.. (2018) Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature, 556 (7702): 501-504. [PMID:29670287]
2. Chapuy B, Roemer MG, Stewart C, Tan Y, Abo RP, Zhang L, Dunford AJ, Meredith DM, Thorner AR, Jordanova ES et al.. (2016) Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood, 127 (7): 869-81. [PMID:26702065]
3. Hörber S, Hildebrand DG, Lieb WS, Lorscheid S, Hailfinger S, Schulze-Osthoff K, Essmann F. (2016) The Atypical Inhibitor of NF-κB, IκBζ, Controls Macrophage Interleukin-10 Expression. J Biol Chem, 291 (24): 12851-61. [PMID:27129283]
4. Johansen C, Mose M, Ommen P, Bertelsen T, Vinter H, Hailfinger S, Lorscheid S, Schulze-Osthoff K, Iversen L. (2015) IκBζ is a key driver in the development of psoriasis. Proc Natl Acad Sci USA, 112 (43): E5825-33. [PMID:26460049]
5. Kayama H, Ramirez-Carrozzi VR, Yamamoto M, Mizutani T, Kuwata H, Iba H, Matsumoto M, Honda K, Smale ST, Takeda K. (2008) Class-specific regulation of pro-inflammatory genes by MyD88 pathways and IkappaBzeta. J Biol Chem, 283 (18): 12468-77. [PMID:18319258]
6. Kimura R, Senba M, Cutler SJ, Ralph SJ, Xiao G, Mori N. (2013) Human T cell leukemia virus type I tax-induced IκB-ζ modulates tax-dependent and tax-independent gene expression in T cells. Neoplasia, 15 (9): 1110-24. [PMID:24027435]
7. Okamoto K, Iwai Y, Oh-Hora M, Yamamoto M, Morio T, Aoki K, Ohya K, Jetten AM, Akira S, Muta T et al.. (2010) IkappaBzeta regulates T(H)17 development by cooperating with ROR nuclear receptors. Nature, 464 (7293): 1381-5. [PMID:20383124]
8. Totzke G, Essmann F, Pohlmann S, Lindenblatt C, Jänicke RU, Schulze-Osthoff K. (2006) A novel member of the IkappaB family, human IkappaB-zeta, inhibits transactivation of p65 and its DNA binding. J Biol Chem, 281 (18): 12645-54. [PMID:16513645]
9. Willems M, Dubois N, Musumeci L, Bours V, Robe PA. (2016) IκBζ: an emerging player in cancer. Oncotarget, 7 (40): 66310-66322. [PMID:27579619]
Inhibitors of NF-kappaB (IκB) family proteins: NFKB inhibitor zeta. Last modified on 04/05/2018. Accessed on 10/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=3008.