NFKBIZ

Summary

NFKBIZ (NFKB inhibitor zeta, HGNC:29805) is a protein-coding gene on chromosome 3q12.3, encoding NF-kappa-B inhibitor zeta (Q9BYH8). Involved in regulation of NF-kappa-B transcription factor complexes.

This gene is a member of the ankyrin-repeat family and is induced by lipopolysaccharide (LPS). The C-terminal portion of the encoded product which contains the ankyrin repeats, shares high sequence similarity with the I kappa B family of proteins. The latter are known to play a role in inflammatory responses to LPS by their interaction with NF-B proteins through ankyrin-repeat domains. Studies in mouse indicate that this gene product is one of the nuclear I kappa B proteins and an activator of IL-6 production. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 64332 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary nonpolyposis colon cancer (Limited, ClinGen)
• GWAS associations: 7
• Clinical variants (ClinVar): 95 total
• MANE Select transcript: NM_031419

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29805
Approved symbol	NFKBIZ
Name	NFKB inhibitor zeta
Location	3q12.3
Locus type	gene with protein product
Status	Approved
Aliases	MAIL, FLJ34463, INAP
Ensembl gene	ENSG00000144802
Ensembl biotype	protein_coding
OMIM	608004
Entrez	64332

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 4 retained_intron

ENST00000326151, ENST00000326172, ENST00000394054, ENST00000461724, ENST00000465476, ENST00000477601, ENST00000483180, ENST00000486444, ENST00000491281, ENST00000495089, ENST00000495719

RefSeq mRNA: 2 — MANE Select: NM_031419 NM_001005474, NM_031419

CCDS: CCDS2946, CCDS43123

Canonical transcript exons

ENST00000326172 — 12 exons

Exon	Start	End
ENSE00000967204	101852738	101852768
ENSE00000967205	101852886	101852989
ENSE00000967207	101854578	101854683
ENSE00000967209	101855395	101855458
ENSE00000967210	101855733	101855902
ENSE00000967211	101857073	101857183
ENSE00000967213	101859318	101861022
ENSE00001248707	101853091	101853863
ENSE00001248779	101849514	101849917
ENSE00003631240	101855062	101855208
ENSE00003694627	101852085	101852224
ENSE00003790744	101857292	101857459

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 99.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 155.3264 / max 13450.4866, expressed in 1816 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37672	145.3153	1815
37663	7.8335	596
37688	0.4530	189
37665	0.4246	121
37664	0.2248	95
37686	0.2230	86
37683	0.1708	52
37662	0.1560	68
37684	0.1475	57
37661	0.1298	48

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	99.91	gold quality
pancreatic ductal cell	CL:0002079	99.91	gold quality
palpebral conjunctiva	UBERON:0001812	99.42	gold quality
upper leg skin	UBERON:0004262	99.04	gold quality
parietal pleura	UBERON:0002400	98.98	gold quality
trachea	UBERON:0003126	98.72	gold quality
visceral pleura	UBERON:0002401	98.68	gold quality
bone marrow cell	CL:0002092	98.66	gold quality
mucosa of stomach	UBERON:0001199	98.53	gold quality
nasal cavity epithelium	UBERON:0005384	98.46	gold quality
monocyte	CL:0000576	98.37	gold quality
nipple	UBERON:0002030	98.32	gold quality
pylorus	UBERON:0001166	98.28	gold quality
left uterine tube	UBERON:0001303	98.22	gold quality
upper arm skin	UBERON:0004263	98.09	gold quality
cartilage tissue	UBERON:0002418	98.01	gold quality
esophagus squamous epithelium	UBERON:0006920	97.99	gold quality
smooth muscle tissue	UBERON:0001135	97.92	gold quality
skin of hip	UBERON:0001554	97.92	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.84	gold quality
penis	UBERON:0000989	97.71	gold quality
germinal epithelium of ovary	UBERON:0001304	97.69	gold quality
oral cavity	UBERON:0000167	97.68	gold quality
duodenum	UBERON:0002114	97.50	gold quality
leukocyte	CL:0000738	97.40	gold quality
ileal mucosa	UBERON:0000331	97.33	gold quality
gingival epithelium	UBERON:0001949	97.13	gold quality
gall bladder	UBERON:0002110	97.09	gold quality
lower lobe of lung	UBERON:0008949	97.04	gold quality
oviduct epithelium	UBERON:0004804	97.01	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	1600.40
E-MTAB-7037	yes	1232.39
E-MTAB-9467	yes	34.87
E-CURD-122	yes	34.68
E-MTAB-9221	yes	33.73
E-HCAD-10	yes	16.46
E-CURD-46	yes	13.48
E-GEOD-137537	yes	6.04
E-MTAB-6678	yes	5.91
E-MTAB-10137	no	1770.62
E-HCAD-13	no	165.56
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
CCL2
DEFB4A	Unknown
IFNG
IL17A	Activation
IL6
LCN2
NCAM1
NFKBIZ
TNF

Upstream regulators (CollecTRI, top): CREB1, NFKB1, NFKB, NFKBIZ, RELA

miRNA regulators (miRDB)

96 targeting NFKBIZ, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-8062	99.88	68.43	995
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-579-3P	99.86	71.66	3628
HSA-LET-7G-3P	99.85	70.43	1929

Literature-anchored findings (GeneRIF, showing 40)

• These results indicate the existence of another signal essential for I kappa B-zeta induction, which is specifically mediated by the Toll/interleukin-1 receptor (TIR) domain-mediated signaling pathway. (PMID:12565889)
• IkappaB-zeta harbors latent transcriptional activation activity which is expressed upon interaction with the NF-kappaB p50 subunit (PMID:15618216)
• IkappaB-zeta functions as an additional regulator of NF-kappaB activity (PMID:16513645)
• IL-1beta specificity is caused by a requirement of the neutrophil gelatinase-associated lipocalin promoter for the NF-kappaB-binding cofactor IkappaB-zeta for transcriptional activation (PMID:16622025)
• IkappaB-zeta acts as an essential transcriptional activator by forming a complex with NF-kappaB on promoters harbouring the NF-kappaB- and C/EBP-binding sites. (PMID:17447895)
• the NF-kappaB binding cofactor, IkappaB-zeta, was up-regulated by IL-17A, and the knockdown of IkappaB-zeta significantly diminished the IL-17A-induced hBD-2 expression. (PMID:18362142)
• I kappaB zeta binds preferentially to NF-kappaB p50 homodimers. (PMID:18436238)
• The nuclear factor NFKBIZ colocalizes with FUS-DDIT3 in nuclear structures. FUS-DDIT3 binds the C-terminal of NFKBIZ. FUS-DDIT3 deregulates some NF-kappaB-controlled genes through interactions with NFKBIZ. (PMID:18850010)
• These results suggest that IkappaB-zeta is a negative regulator of STAT3, and demonstrate a novel mechanism in which a component of the NF-kappaB signaling pathway inhibits the activation of STAT3. (PMID:19595668)
• silencing of IkappaBzeta expression led to a specific decrease in IFNgamma production. Overall, our data suggests that IkappaBzeta positively regulates NFkappaB-mediated IFNgamma production in KG-1 cells (PMID:19707556)
• MAIL is a key regulator of IL-6 production in human monocytes and plays an important role in both TLR and NOD-like receptor ligand induced inflammation. (PMID:19783680)
• conclude that multiple NFKBIZ polymorphisms associate with susceptibility to IPD in humans. The study of multiple populations may aid in fine mapping of associations within extensive regions of strong linkage disequilibrium (PMID:19798075)
• analysis of the sequence of flagellin/TLR5- and type IV-dependent IkappaBzeta expression, recruitment of IkappaBzeta/p50 to the il6 promoter, chromatin remodelling and subsequent IL-6 transcription in L. pneumophila-infected lung epithelial cells (PMID:20650996)
• IkappaBzeta functions as an important regulator of IFN-gamma in human NK cells (PMID:21224476)
• investigation of signaling components that induce activation of post-transcriptional mechanism for IkappaB-zeta induction/activation: Activation of IRAK1 or IRAK4, but not TRAF6, is sufficient. (PMID:22059479)
• our data demonstrate that IkappaB-zeta is essential for nuclear NF-kappaB activity in activated B-cell-like subtype of diffuse large B-cell lymphoma (PMID:23869088)
• NF-kappaB-binding cofactor inhibitor of NF-kappaB-zeta (IkappaB-zeta) is constitutively expressed in HTLV-I-infected T cell lines and ATL cells, and Tax transactivates the IkappaB-zeta gene, mainly through NF-kappaB. (PMID:24027435)
• Interferon-gamma (IFN-gamma) interferes with the IL-1/IKB-zeta axis in beta-glucan-activated dendritic cells and promotes T cell-mediated immune responses with increased release of IFN-gamma and IL-22. (PMID:25474109)
• NFKBIZ gene knockdown in bronchial epithelial cells suppresses the release of IL-1b-induced IL-6 and GMCSF. (PMID:25629767)
• We propose a previously unappreciated role of IkappaBzeta in the inflammatory micromilieu as well as progression in glioma (PMID:26398661)
• These results indicate that the LPS/IL-1beta-MyD88 axis plays a crucial role for stabilization of IkappaB-zeta mRNA. (PMID:26711529)
• a specific IL-17A-induced gene, NFKBIZ, which encodes IkappaB-zeta, a transcriptional regulator for NF-kappaB, was demonstrated to have a significant role for IL-17A-induced gene expression. (PMID:26944069)
• TNF-alpha- and IL-17A mediate synergistic induction of DEFB4 gene expression in human keratinocytes through IkappaBzeta (PMID:27117051)
• we demonstrate that IkappaBzeta, a transcriptional co-activator, may play an important role in psoriasis and possibly other inflammatory diseases by mediating IL-17F- driven effects. (PMID:27576147)
• IkappaB-zeta regulates human monocyte pro-inflammatory responses induced by Streptococcus pneumoniae. (PMID:27597997)
• this study shows association of common intragenic NFKBIZ polymorphisms with the risk of developing psoriasis (PMID:28259733)
• In cultured macrophages, LPS-induced expression of monocyte chemoattractant protein (MCP)-1 was suppressed by NaN3 through inhibition of STAT1 and IkappaBzeta activities. (PMID:28391993)
• electrophilic properties of itaconate and derivatives regulate the IkappaBzeta-ATF3 inflammatory axis; results demonstrate that targeting the DI-IkappaBzeta regulatory axis could be an important new strategy for the treatment of IL-17-IkappaBzeta-mediated autoimmune diseases (PMID:29670287)
• In conclusion, we present IkappaBzeta as a novel key regulator of IL-17A/ F-driven effects in psoriasis. (PMID:29938836)
• Our study supported a significant effect of a common NFKBIZ polymorphism on the response to adalimumab. This result could help to optimize the prescription of this anti-TNF, but requires confirmation in other cohorts. (PMID:31267486)
• results define a crucial role for IkappaBzeta in the antipsoriatic effect of secukinumab. Because IkappaBzeta signature genes were regulated already after 4 days of treatment, this strongly indicates that IkappaBzeta plays a crucial role in the antipsoriatic effects mediated by anti-IL-17A treatment. (PMID:31622687)
• found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells (PMID:31853061)
• Threonine Phosphorylation of IkappaBzeta Mediates Inhibition of Selective Proinflammatory Target Genes. (PMID:32035922)
• In fibroblasts, IL-17A response depends on CUX1 and IkappaBzeta to engage the NF-kappaB complex to produce chemoattractants for neutrophil and monocyte recruitment. (PMID:32079724)
• IkBzeta is a Key Regulator of Tumour Necrosis Factor-a and Interleukin-17A-mediated Induction of Interleukin-36g in Human Keratinocytes. (PMID:33491092)
• Upregulation of NFKBIZ affects bladder cancer progression via the PTEN/PI3K/Akt signaling pathway. (PMID:33907827)
• PFN1 Prevents Psoriasis Pathogenesis through IkappaBzeta Regulation. (PMID:35148999)
• Genetic variants in the NF-kappaB signaling pathway (NFKB1, NFKBIA, NFKBIZ) and risk of critical outcome among COVID-19 patients. (PMID:35777990)
• Emerging role of IkappaBzeta in inflammation: Emphasis on psoriasis. (PMID:36245291)
• IkappaBzeta is an essential mediator of immunity to oropharyngeal candidiasis. (PMID:37725983)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfkbiz	ENSDARG00000102097
mus_musculus	Nfkbiz	ENSMUSG00000035356
rattus_norvegicus	Nfkbiz	ENSRNOG00000031163

Paralogs (3): RFXANK (ENSG00000064490), ANKRA2 (ENSG00000164331), NFKBID (ENSG00000167604)

Protein

Protein identifiers

NF-kappa-B inhibitor zeta — Q9BYH8 (reviewed: Q9BYH8)

Alternative names: I-kappa-B-zeta, IL-1 inducible nuclear ankyrin-repeat protein, Molecule possessing ankyrin repeats induced by lipopolysaccharide

All UniProt accessions (5): Q9BYH8, C9J5G8, C9J5I7, C9JZ23, H7C5S1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in regulation of NF-kappa-B transcription factor complexes. Inhibits NF-kappa-B activity without affecting its nuclear translocation upon stimulation. Inhibits DNA-binding of RELA and NFKB1/p50, and of the NF-kappa-B p65-p50 heterodimer and the NF-kappa-B p50-p50 homodimer. Also seems to activate NF-kappa-B-mediated transcription. In vitro, upon association with NFKB1/p50 has transcriptional activation activity and, together with NFKB1/p50 and RELA, is recruited to LCN2 promoters. Promotes transcription of LCN2 and DEFB4. Is recruited to IL-6 promoters and activates IL-6 but decreases TNF production in response to LPS. Seems to be involved in the induction of inflammatory genes activated through TLR/IL-1 receptor signaling. Involved in the induction of T helper 17 cells (Th17) differentiation upon recognition of antigen by T cell antigen receptor (TCR).

Subunit / interactions. Interacts with NFKB1/p50. Interacts with RELA. Interacts with AKIRIN2.

Subcellular location. Nucleus.

Tissue specificity. Expressed at high levels in peripheral blood leukocytes and lung, at moderate levels in liver, placenta, and at low levels in spleen, kidney, skeletal muscle and heart.

Induction. By TNF, IL1/interleukin-1 and bacterial lipopolysaccharides (LPS).

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BYH8-1	1, MAIL-L	yes
Q9BYH8-2	2, MAIL-S, Transcription variant 3
Q9BYH8-3	3

RefSeq proteins (2): NP_001005474, NP_113607* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR047571	OCA	Domain

Pfam: PF12796

UniProt features (43 total): helix 16, repeat 7, region of interest 5, compositionally biased region 4, splice variant 2, strand 2, turn 2, chain 1, domain 1, short sequence motif 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9BOR	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYH8-F1	58.01	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 582 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, LU_IL4_SIGNALING, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE

GO Biological Process (51): toll-like receptor signaling pathway (GO:0002224), plasma cell differentiation (GO:0002317), T cell mediated immunity (GO:0002456), chronic inflammatory response (GO:0002544), chromatin remodeling (GO:0006338), response to xenobiotic stimulus (GO:0009410), regulation of gene expression (GO:0010468), cytokine-mediated signaling pathway (GO:0019221), keratinocyte differentiation (GO:0030216), keratinocyte activation (GO:0032980), B cell proliferation (GO:0042100), mRNA transcription by RNA polymerase II (GO:0042789), keratinocyte proliferation (GO:0043616), T-helper 1 cell differentiation (GO:0045063), isotype switching (GO:0045190), positive regulation of transcription by RNA polymerase II (GO:0045944), spleen development (GO:0048536), homeostasis of number of cells within a tissue (GO:0048873), positive regulation of inflammatory response (GO:0050729), defense response to Gram-negative bacterium (GO:0050829), T cell receptor signaling pathway (GO:0050852), response to folic acid (GO:0051593), establishment of skin barrier (GO:0061436), transcription preinitiation complex assembly (GO:0070897), cellular response to lipopolysaccharide (GO:0071222), cellular response to transforming growth factor beta stimulus (GO:0071560), T-helper 17 cell differentiation (GO:0072539), response to cisplatin (GO:0072718), inflammatory response to wounding (GO:0090594), execution phase of apoptosis (GO:0097194), cellular response to interleukin-17 (GO:0097398), response to Gram-positive bacterium (GO:0140459), epithelial cell apoptotic process (GO:1904019), B cell receptor apoptotic signaling pathway (GO:1990117), positive regulation of T-helper 17 cell differentiation (GO:2000321), adaptive immune response (GO:0002250), lymphocyte activation involved in immune response (GO:0002285), chromatin organization (GO:0006325), transcription by RNA polymerase II (GO:0006366), inflammatory response (GO:0006954)

GO Molecular Function (5): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), transcription coregulator activity (GO:0003712), POU domain binding (GO:0070974), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nuclear speck (GO:0016607), cytoplasmic ribonucleoprotein granule (GO:0036464)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inflammatory response	2
transcription by RNA polymerase II	2
pattern recognition receptor signaling pathway	1
mature B cell differentiation involved in immune response	1
lymphocyte mediated immunity	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
chromatin organization	1
response to chemical	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
epidermal cell differentiation	1
skin development	1
cell activation	1
B cell activation	1
lymphocyte proliferation	1
mRNA transcription	1
epithelial cell proliferation	1
alpha-beta T cell activation involved in immune response	1
T cell differentiation involved in immune response	1
T-helper 1 type immune response	1
T-helper cell differentiation	1
somatic recombination of immunoglobulin genes involved in immune response	1
B cell activation involved in immune response	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
hematopoietic or lymphoid organ development	1
tissue homeostasis	1
homeostasis of number of cells	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
defense response to bacterium	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
transcription regulator activity	1
protein domain specific binding	1
nucleic acid binding	1
binding	1

Protein interactions and networks

STRING

2188 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFKBIZ	AKIRIN2	Q53H80	924
NFKBIZ	REL	Q04864	808
NFKBIZ	RELB	Q01201	806
NFKBIZ	NFKB1	P19838	805
NFKBIZ	PLAAT5	Q96KN8	790
NFKBIZ	STAT3	P40763	764
NFKBIZ	NFKBIE	O00221	704
NFKBIZ	NFKB2	Q00653	692
NFKBIZ	RELA	Q04206	670
NFKBIZ	NFKBIB	Q15653	651
NFKBIZ	ZC3H12A	Q5D1E8	598
NFKBIZ	CEBPD	P49716	595
NFKBIZ	TRAF3IP2	O43734	587
NFKBIZ	TNFAIP3	P21580	577
NFKBIZ	NFKBIA	P25963	572

IntAct

9 interactions, top by confidence:

A	B	Type	Score
NFKBIZ	Akirin2	psi-mi:“MI:0915”(physical association)	0.560
NFKBIZ	Akirin2	psi-mi:“MI:0914”(association)	0.560
NFKBIZ	ERP29	psi-mi:“MI:0915”(physical association)	0.400
NFKB2	NFKBIZ	psi-mi:“MI:0915”(physical association)	0.370
NFKBIZ	NFKB1	psi-mi:“MI:0915”(physical association)	0.370
NFKBIZ	STAT3	psi-mi:“MI:0915”(physical association)	0.370
Akirin2	NFKB1	psi-mi:“MI:0914”(association)	0.350
NFKBIZ	IL6	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): NFKBIZ (Affinity Capture-MS), NFKBIZ (Affinity Capture-MS), NFKBIZ (Affinity Capture-MS), NFKBIZ (Affinity Capture-RNA), NFKBIZ (Affinity Capture-RNA), NFKBIZ (Proximity Label-MS), NFKBIZ (Affinity Capture-RNA), NFKB1 (Affinity Capture-Western), NFKBIZ (Affinity Capture-RNA), NFKBIZ (Two-hybrid), NFKBIZ (Two-hybrid), NFKBIZ (Affinity Capture-Western), STAT3 (Affinity Capture-Western), NFKBIZ (Phenotypic Suppression), NFKBIZ (Two-hybrid)

ESM2 similar proteins: A0A0G2JTY4, A2VD01, A5PMU4, A8E4V2, D2HNW6, E1BEQ5, O54972, O95644, P16236, P59281, P70365, P97305, Q12968, Q13191, Q13469, Q13905, Q15788, Q1LY51, Q2VPU4, Q3LRZ1, Q3TTA7, Q3U182, Q4PJW2, Q4VCS5, Q60591, Q61122, Q66IV1, Q68FF7, Q6DFR2, Q6GQL0, Q6NYU6, Q6ZNC4, Q80TM6, Q80VG1, Q8HWS3, Q8IXK0, Q8IY63, Q8K4S7, Q8N228, Q8VHG2

Diamond homologs: A2RUV0, G3I6Z6, O00221, O35516, O54910, O73630, P19838, P20749, P21783, P25963, P46530, P46531, P98150, Q00653, Q01317, Q01705, Q04721, Q04861, Q07008, Q08353, Q08DV6, Q15653, Q18297, Q2TB02, Q5R4M7, Q5ZLC8, Q60778, Q61982, Q63369, Q63746, Q6F3J0, Q8BTI7, Q8NB46, Q9BE45, Q9BYH8, Q9EST8, Q9JIA3, Q9NWX5, Q9QW30, Q9R172

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NFKBIZ	“up-regulates quantity by expression”	IL17A	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

95 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	65
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1379 predictions. Top by Δscore:

Variant	Effect	Δscore
3:101850481:G:GT	donor_gain	1.0000
3:101852078:T:TA	acceptor_gain	1.0000
3:101852081:ACAGT:A	acceptor_loss	1.0000
3:101852082:CAGTT:C	acceptor_loss	1.0000
3:101852083:A:AG	acceptor_gain	1.0000
3:101852083:AGTT:A	acceptor_gain	1.0000
3:101852084:G:GT	acceptor_gain	1.0000
3:101852084:GT:G	acceptor_gain	1.0000
3:101852084:GTT:G	acceptor_gain	1.0000
3:101852084:GTTG:G	acceptor_gain	1.0000
3:101852084:GTTGA:G	acceptor_gain	1.0000
3:101852220:TTAAG:T	donor_loss	1.0000
3:101852221:TAAG:T	donor_loss	1.0000
3:101852222:AAG:A	donor_loss	1.0000
3:101852223:AGGT:A	donor_loss	1.0000
3:101852224:GGTG:G	donor_loss	1.0000
3:101852225:G:T	donor_loss	1.0000
3:101852226:T:A	donor_loss	1.0000
3:101852736:A:AG	acceptor_gain	1.0000
3:101852737:G:GG	acceptor_gain	1.0000
3:101852878:G:A	acceptor_gain	1.0000
3:101852884:A:AG	acceptor_gain	1.0000
3:101852885:G:GG	acceptor_gain	1.0000
3:101852885:GA:G	acceptor_gain	1.0000
3:101852885:GAATT:G	acceptor_gain	1.0000
3:101852985:TTTTG:T	donor_gain	1.0000
3:101852990:G:GG	donor_gain	1.0000
3:101853230:TTC:T	donor_gain	1.0000
3:101853864:G:GG	donor_gain	1.0000
3:101854567:A:AG	acceptor_gain	1.0000

AlphaMissense

4735 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:101857314:T:A	L653H	1.000
3:101857326:C:A	A657D	1.000
3:101857362:T:A	V669D	1.000
3:101857371:T:C	L672S	1.000
3:101857405:C:A	N683K	1.000
3:101857405:C:G	N683K	1.000
3:101857422:C:A	P689Q	1.000
3:101859331:T:C	L706P	1.000
3:101854595:T:A	V452D	0.999
3:101854603:G:T	G455W	0.999
3:101854628:T:C	L463P	0.999
3:101855078:C:A	A487E	0.999
3:101855114:T:C	L499P	0.999
3:101855146:G:C	D510H	0.999
3:101855180:C:A	A521D	0.999
3:101855757:T:A	V560D	0.999
3:101855871:T:C	L598P	0.999
3:101857109:G:C	A621P	0.999
3:101857110:C:A	A621D	0.999
3:101857311:C:A	A652D	0.999
3:101857314:T:C	L653P	0.999
3:101857323:C:A	A656D	0.999
3:101857325:G:C	A657P	0.999
3:101857368:T:C	L671P	0.999
3:101857386:C:A	A677E	0.999
3:101857389:A:G	D678G	0.999
3:101857422:C:G	P689R	0.999
3:101857434:T:A	V693D	0.999
3:101859331:T:A	L706Q	0.999
3:101852126:T:C	F111L	0.998

dbSNP variants (sampled 300 via entrez): RS1000263983 (3:101853551 C>A,T), RS1000389583 (3:101826707 G>A), RS1000415953 (3:101860602 T>C), RS1000464754 (3:101858868 G>C), RS1000470538 (3:101860324 G>A), RS1000537403 (3:101827838 C>G,T), RS1000550196 (3:101840237 C>T), RS1000700513 (3:101848412 C>G), RS1000831716 (3:101841530 A>G), RS1001217412 (3:101834411 A>G), RS1001286636 (3:101840185 G>C), RS1001287949 (3:101827680 C>G), RS1001393851 (3:101828218 A>G), RS1001400613 (3:101840675 C>T), RS1001667435 (3:101833036 G>A)

Disease associations

OMIM: gene MIM:608004 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary nonpolyposis colon cancer	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hereditary nonpolyposis colon cancer	Limited	AD

Mondo (1): hereditary nonpolyposis colon cancer (MONDO:0018630)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001198_53	Multiple sclerosis	9.000000e-09
GCST002889_3	Psoriasis	2.000000e-10
GCST003045_4	Ulcerative colitis	9.000000e-06
GCST003268_2	Psoriasis vulgaris	7.000000e-08
GCST003268_35	Psoriasis vulgaris	4.000000e-08
GCST003270_14	Psoriatic arthritis	9.000000e-08
GCST009307_7	Spatial memory	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:1001494	psoriasis vulgaris
EFO:0004874	memory performance

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Inhibitors of NF-kappaB (IκB) family proteins

CTD chemical–gene interactions

91 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases expression, decreases expression, affects cotreatment, increases abundance, affects expression	5
Valproic Acid	decreases expression, decreases methylation, increases expression, affects expression	4
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	3
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
bisphenol A	decreases expression, increases methylation	2
bisphenol S	increases expression, affects methylation	2
(+)-JQ1 compound	decreases expression, increases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Vehicle Emissions	decreases expression, affects expression, increases reaction, affects cotreatment	2
Bleomycin	decreases reaction, increases expression	2
Estradiol	decreases expression, decreases reaction	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression	2
Asbestos, Crocidolite	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
Particulate Matter	increases expression, affects expression, increases reaction, increases abundance	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
Glupearl 19S	increases expression	1
TL8-506	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
sanguinarine	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1

Clinical trials (associated diseases)

14 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00141466	Not specified	UNKNOWN	Implementation of a New Strategy to Identify HNPCC Patients
NCT00262171	Not specified	UNKNOWN	Hereditary Nonpolyposis Colorectal Cancer in Taiwan-Related Genetic Study and Clinical Applications
NCT00341575	Not specified	COMPLETED	Psychosocial Aspects of Genetic Testing for Hereditary Nonpolyposis Colon Cancer
NCT00508573	Not specified	COMPLETED	Registry for Women Who Are At Risk Or May Have Lynch Syndrome
NCT01216930	Not specified	COMPLETED	Molecular Screening for Lynch Syndrome in Southern Denmark
NCT01646112	Not specified	COMPLETED	Uncertain Genetic Test Results for Lynch Syndrome
NCT01823471	Not specified	COMPLETED	I-Scan For Colon Polyp Detection In HNPCC
NCT01845753	Not specified	COMPLETED	Molecular Screening for Lynch Syndrome in Denmark
NCT02198092	Not specified	COMPLETED	Preliminary Evaluation of Septin9 in Patients With Hereditary Colon Cancer Syndromes
NCT02206360	Not specified	ACTIVE_NOT_RECRUITING	Pancreatic Cancer Early Detection Program
NCT03303833	Not specified	RECRUITING	The GEOLynch Cohort Study
NCT06426927	Not specified	COMPLETED	PeLear CCC: Proyecto Latino Contra Cancer Colorrectal
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06989814	Not specified	RECRUITING	Smart Measurement of Circulating Tumor DNA