NFKB inhibitor zeta

Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 3008

Nomenclature: NFKB inhibitor zeta

Abbreviated Name: IκBζ

Family: Inhibitors of NF-kappaB (IκB) family proteins

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).

Previous and Unofficial Names
nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, zeta \| nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor \| IL-1 inducible nuclear ankyrin-repeat protein \| molecule possessing ankyrin repeats induced by lipopolysaccharide \| NF-kappa-B inhibitor zeta \| nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta \| MAIL \| INAP

Previous and Unofficial Names

nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, zeta | nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor | IL-1 inducible nuclear ankyrin-repeat protein | molecule possessing ankyrin repeats induced by lipopolysaccharide | NF-kappa-B inhibitor zeta | nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta | MAIL | INAP

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].

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

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Immune system development

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Chemotaxis & migration

Immuno Process:

Cellular signalling

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].

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].

References

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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]

How to cite this page

Inhibitors of NF-kappaB (IκB) family proteins: NFKB inhibitor zeta. Last modified on 04/05/2018. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3008.

NFKB inhibitor zeta

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