RELB

Summary

RELB (RELB proto-oncogene, NF-kB subunit, HGNC:9956) is a protein-coding gene on chromosome 19q13.32, encoding Transcription factor RelB (Q01201). NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis.

Enables RNA polymerase II cis-regulatory region sequence-specific DNA binding activity and protein kinase binding activity. Involved in lymphocyte differentiation and negative regulation of interferon-beta production. Located in several cellular components, including centrosome; chromatin; and nucleoplasm. Part of nucleus and transcription repressor complex. Implicated in breast cancer and immunodeficiency 53. Biomarker of breast cancer and transitional cell carcinoma.

Source: NCBI Gene 5971 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 53 (Strong, GenCC)
• GWAS associations: 29
• Clinical variants (ClinVar): 512 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes
• Transcription factor: yes — 65 downstream targets (CollecTRI)
• MANE Select transcript: NM_006509

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9956
Approved symbol	RELB
Name	RELB proto-oncogene, NF-kB subunit
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	REL-B
Ensembl gene	ENSG00000104856
Ensembl biotype	protein_coding
OMIM	604758
Entrez	5971

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000221452, ENST00000505236, ENST00000509229, ENST00000509480, ENST00000510184, ENST00000589972, ENST00000700471

RefSeq mRNA: 2 — MANE Select: NM_006509 NM_001411087, NM_006509

CCDS: CCDS46110, CCDS92640

Canonical transcript exons

ENST00000221452 — 12 exons

Exon	Start	End
ENSE00000712169	45022053	45022210
ENSE00000712176	45025606	45025737
ENSE00000712180	45028888	45028992
ENSE00000712184	45032534	45032749
ENSE00000712188	45034244	45034312
ENSE00000712192	45034451	45034528
ENSE00000861668	45011936	45012276
ENSE00000861669	45002949	45002996
ENSE00001048624	45001464	45001685
ENSE00001048628	45037405	45038192
ENSE00003504631	45009814	45009822
ENSE00003564882	45025329	45025420

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 89.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.6218 / max 302.6389, expressed in 1571 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176373	10.6218	1571

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	89.73	gold quality
mucosa of transverse colon	UBERON:0004991	89.16	gold quality
cartilage tissue	UBERON:0002418	88.43	gold quality
monocyte	CL:0000576	87.21	gold quality
leukocyte	CL:0000738	86.87	gold quality
mononuclear cell	CL:0000842	86.77	gold quality
spleen	UBERON:0002106	86.33	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.49	gold quality
blood	UBERON:0000178	83.78	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.00	gold quality
upper lobe of left lung	UBERON:0008952	82.94	gold quality
stromal cell of endometrium	CL:0002255	82.50	gold quality
omental fat pad	UBERON:0010414	82.32	gold quality
peritoneum	UBERON:0002358	82.21	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.01	gold quality
vermiform appendix	UBERON:0001154	81.92	gold quality
lymph node	UBERON:0000029	81.73	gold quality
skin of abdomen	UBERON:0001416	81.66	gold quality
gastrocnemius	UBERON:0001388	81.58	gold quality
left uterine tube	UBERON:0001303	81.54	gold quality
transverse colon	UBERON:0001157	81.30	gold quality
skin of leg	UBERON:0001511	81.30	gold quality
body of uterus	UBERON:0009853	80.94	gold quality
left adrenal gland	UBERON:0001234	80.89	gold quality
small intestine	UBERON:0002108	80.83	gold quality
apex of heart	UBERON:0002098	80.77	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.73	gold quality
sural nerve	UBERON:0015488	80.41	gold quality
left adrenal gland cortex	UBERON:0035825	80.20	gold quality
body of stomach	UBERON:0001161	80.18	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-95	yes	494.03
E-HCAD-8	yes	44.94
E-GEOD-135922	yes	10.06
E-ANND-3	yes	7.09
E-GEOD-99795	no	12.85

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

65 targets.

Target	Regulation
ABCB1	Activation
AHR	Unknown
AQP2
AR
ATP11C
BCL10
BCL2	Activation
BCL2L1
BECN1
BIRC3	Unknown
CBX5
CCL1	Activation
CCL17	Activation
CCL19	Activation
CCL20	Activation
CCL21	Activation
CCL22	Repression
CCL5	Activation
CCND1	Activation
CD40	Unknown
CD80	Unknown
CD86	Unknown
CD8A
CDKN1A	Unknown
CFLAR
CHUK
CLPP
CLPX
CNTN2
CRH

JASPAR motifs

Motif	Name	Family
MA1117.1	RELB	NF-kappaB-related factors
MA1117.2	RELB	NF-kappaB-related factors

JASPAR matrix evidence (PMIDs): PMID:17996728

Upstream regulators (CollecTRI, top): AP1, ARNT, ESR1, FOS, FOSL2, JUN, NFKB1, NFKB2, NFKB, NOTCH1, RBPJ, REL, RELA, RELB, VDR

Literature-anchored findings (GeneRIF, showing 40)

• Rel activity plays role in regulation of apoptosis in hepatocellular carcinoma through activation of downstream target genes (PMID:12365017)
• During dendritic cell maturation, rapidly activated dimers (e.g., RelA) bound to a subset of target promoters are gradually replaced by slowly activated dimers (e.g., RelB). (PMID:12820969)
• RelB has an effect on p100 processing, which is possibly regulated in a signal-dependent manner (PMID:12874295)
• RelB mediates TNF-induced up-regulation of the human polymeric Ig receptor. (PMID:15265917)
• RelB overexpression promoted, whereas endogenous RelB inhibition (by p100DeltaN) blocked, precursor cell development along this DC subset pathway. (PMID:15315978)
• induced by cytomegalovirus (CMV) immediate-early 1 protein via activation of JNK and AP-1 (PMID:15596805)
• RelB expression during dendritic cells differentiation is controlled by protein kinase CbetaII-mediated regulation of transcriptional initiation and elongation (PMID:16107733)
• Plays an important role in redox regulation of the cell and protects aggressive prostate cancer cells against radiation-induced cell death. (PMID:16261162)
• The roles of RAC1 and RAC1b in the RelB mediated transciption in 3 tumor cell lines are reported. (PMID:16551621)
• IKKalpha regulates growth pathway involving the p52/RelB-dependent transcriptional regulation of the skp2 gene. (PMID:16902410)
• RelB can repress proinflammatory gene expression and may play a role in the endotoxin-tolerant phenotype in the blood leukocytes of sepsis patients. (PMID:16951372)
• RelB plays a previously unrecognized negative regulatory role upon specific Langerhans cell activation. (PMID:16960152)
• Data demonstrate that CD40 signals B cell survival in part via transcriptional activation of the RelB NF-kappaB subunit. (PMID:17446175)
• aryl hydrocarbon receptor with NF-kappaB RelB signaling pathways represent a new mechanism of cross talk between the two transcription factors (PMID:17823304)
• The interaction of AhR with RelB binding on a novel type of NF-kappaB binding site represents a new regulatory function of the AhR. (PMID:17900530)
• RelB is differentially regulated by IkappaB Kinase-alpha in B cells and mouse lung by cigarette smoke (PMID:18688039)
• The authors conclude that RelB functions as a dual transcription regulator during LPS tolerance and human severe systemic inflammation by activating and repressing innate immunity genes. (PMID:19020113)
• identification of aryl hydrocarbon nuclear translocator(ARNT) as a CD30-interacting protein that modulated activity of the RelB subunit of NF-kappaB; findings indicate ARNT functions in concert with RelB in a CD30-induced negative feedback mechanism (PMID:19131627)
• Inhibiting RelB in aggressive androgen-independent PC-3 cells by stable or conditional expression of a dominant-negative p100 mutant significantly reduced the incidence and growth rate of tumors. (PMID:19351823)
• Inhibition of RelB by 1,25-dihydroxyvitamin D3 promotes sensitivity of breast cancer cells to radiation. (PMID:19373868)
• the induction of Blimp1 represents a novel mechanism whereby the RelB NF-kappaB subunit mediates repression, specifically of ERalpha, thereby promoting a more migratory phenotype in breast cancer cells (PMID:19433448)
• Results demonstrated that RelB/p50 was active only in DC expressing both RelB and p50, and induced CCL19 production, but not DC maturation. (PMID:19655301)
• Data show that RelB induces facultative heterochromatin formation by directly interacting with the histone H3 lysine 9 methyltransferase G9a. (PMID:19690169)
• the results suggest that RelB was responsible for the LPS-mediated attachment and may play an important role in the progression of some cancers. (PMID:19903458)
• the Tio oncoprotein triggers noncanonical NF-kappaB signaling through NEMO-dependent up-regulation of p100 precursor and RelB, as well as through NEMO-independent generation of p52 effector (PMID:20353939)
• REQ functions as an efficient adaptor protein between the SWI/SNF complex and RelB/p52 and plays important roles in noncanonical NF-kappaB transcriptional activation and its associated oncogenic activity. (PMID:20460684)
• The deregulation of NF-kappaB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer (PMID:20564628)
• Bovine foamy virus transactivator BTas interacts with cellular RelB to enhance viral transcription. (PMID:20844054)
• epigenetic RELB silencing as a new marker of the progressive disease in males (PMID:21062507)
• Data show that RelB is inducibly phosphorylated by GSK-3beta, indicating a direct substrate-enzyme relationship. (PMID:21217772)
• Data show that intracellular dsRNA signaling was dependent on RELA, but not RELB. (PMID:21310030)
• AHR overexpression is found among estrogen receptor (ER)alpha-negative human breast tumors and that its overexpression is positively correlated to that of the NF-kappaB subunit Rel-B and Interleukin 8. (PMID:21640702)
• We propose that RelB is an essential molecule controlling the endogenous and the proteasome inhibitor-induced Maspin expression. (PMID:21856005)
• a central role for Malt1-dependent RelB cleavage in canonical NF-kappaB activation and thereby provide a rationale for the targeting of Malt1 in immunomodulation and cancer treatment. (PMID:21873235)
• Nuclear factor kappaB subunits RelB and cRel negatively regulate Toll-like receptor 3-mediated beta-interferon production via induction of transcriptional repressor protein YY1. (PMID:22065573)
• RelB is a CO(2)-sensitive NF-kappaB family member that may contribute to the beneficial effects of hypercapnia in inflammatory diseases of the lung (PMID:22396550)
• RelB plays a critical role in the response of PCa to radiotherapy and the inverse expression of IL-8 and PSA (PMID:22403723)
• women entering labor exhibit low or moderate NFkappaB activition, the process does not appear to involve classical pathways of NFkappaB activation but rather is correlated with an increase in nuclear p65-Rel-B dimers. (PMID:22485186)
• RelB/NF-kappaB2, is constitutively activated in the human placenta, which binds to a previously undescribed NF-kappaB enhancer of corticotropin-releasing hormone (CRH) gene promoter to regulate CRH expression. (PMID:22734038)
• a novel link between NF-kappaB and growth-inhibitory pathways involving the RelB-dependent transcriptional upregulation of p53. (PMID:22777360)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	relb	ENSDARG00000086173
mus_musculus	Relb	ENSMUSG00000002983
rattus_norvegicus	Relb	ENSRNOG00000033235
drosophila_melanogaster	Dif	FBGN0011274
drosophila_melanogaster	dl	FBGN0260632

Paralogs (4): NFKB2 (ENSG00000077150), NFKB1 (ENSG00000109320), REL (ENSG00000162924), RELA (ENSG00000173039)

Protein

Protein identifiers

Transcription factor RelB — Q01201 (reviewed: Q01201)

Alternative names: I-Rel

All UniProt accessions (5): Q01201, A0A8V8TQY2, D6R992, D6RIV7, K7ERX9

UniProt curated annotations — full annotation on UniProt →

Function. NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric RelB-p50 and RelB-p52 complexes are transcriptional activators. RELB neither associates with DNA nor with RELA/p65 or REL. Stimulates promoter activity in the presence of NFKB2/p49. As a member of the NUPR1/RELB/IER3 survival pathway, may provide pancreatic ductal adenocarcinoma with remarkable resistance to cell stress, such as starvation or gemcitabine treatment. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer in a CRY1/CRY2 independent manner. Increased repression of the heterodimer is seen in the presence of NFKB2/p52. Is required for both T and B lymphocyte maturation and function.

Subunit / interactions. Component of the NF-kappa-B RelB-p50 complex. Component of the NF-kappa-B RelB-p52 complex. Self-associates; the interaction seems to be transient and may prevent degradation allowing for heterodimer formation with p50 or p52. Interacts with NFKB1/p50, NFKB2/p52 and NFKB2/p100. Interacts with NFKBID. Interacts with BMAL1 and the interaction is enhanced in the presence of CLOCK.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Post-translational modifications. Phosphorylation at ‘Thr-103’ and ‘Ser-573’ is followed by proteasomal degradation.

Disease relevance. Immunodeficiency 53 (IMD53) [MIM:617585] An autosomal recessive primary immunodeficiency apparent from early infancy and resulting in recurrent infections, severe autoimmune skin disease rheumatoid arthritis, and failure to thrive. Immunologic workup shows increased CD4+/CD8+ ratio, impaired T-cell proliferative response to multiple antigen, T-cell developmental and functional defects, and impaired ability to produce specific immunoglobulins. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Both N- and C-terminal domains are required for transcriptional activation.

Induction. Up-regulated by mitogens and NUPR1.

RefSeq proteins (2): NP_001398016, NP_006500* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000451	NFkB/Dor	Family
IPR002909	IPT_dom	Domain
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR011539	RHD_DNA_bind_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR030492	RHD_CS	Conserved_site
IPR030496	RelB_RHD_N	Domain
IPR032397	RHD_dimer	Domain
IPR032399	RelB_leu_zip	Domain
IPR032400	RelB_transact	Domain
IPR033926	IPT_NFkappaB	Domain
IPR037059	RHD_DNA_bind_dom_sf	Homologous_superfamily

Pfam: PF00554, PF16179, PF16180, PF16181

UniProt features (12 total): modified residue 3, sequence conflict 2, region of interest 2, sequence variant 2, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8G8R	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01201-F1	70.42	0.44

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 16, 37, 573

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling
R-HSA-5621575	CD209 (DC-SIGN) signaling
R-HSA-5676590	NIK–>noncanonical NF-kB signaling

MSigDB gene sets: 402 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CIRCADIAN_RHYTHM, CREL_01, GOBP_DENDRITIC_CELL_DIFFERENTIATION, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, KEGG_MAPK_SIGNALING_PATHWAY, MODULE_522, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION

GO Biological Process (19): inflammatory response (GO:0006954), canonical NF-kappaB signal transduction (GO:0007249), antigen processing and presentation (GO:0019882), lymphocyte differentiation (GO:0030098), negative regulation of interferon-beta production (GO:0032688), circadian regulation of gene expression (GO:0032922), response to cytokine (GO:0034097), non-canonical NF-kappaB signal transduction (GO:0038061), myeloid dendritic cell differentiation (GO:0043011), T-helper 1 cell differentiation (GO:0045063), innate immune response (GO:0045087), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), cellular response to osmotic stress (GO:0071470), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), negative regulation of macromolecule biosynthetic process (GO:0010558), T-helper 1 type immune response (GO:0042088), rhythmic process (GO:0048511)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (11): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), transcription repressor complex (GO:0017053), protein-containing complex (GO:0032991), synapse (GO:0045202), NF-kappaB complex (GO:0071159), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
CLEC7A (Dectin-1) signaling	1
C-type lectin receptors (CLRs)	1
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular signaling cassette	2
regulation of gene expression	2
DNA-templated transcription	2
regulation of DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
regulation of macromolecule biosynthetic process	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
defense response	1
immune system process	1
lymphocyte activation	1
mononuclear cell differentiation	1
negative regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
circadian rhythm	1
response to peptide	1
myeloid dendritic cell activation	1
myeloid leukocyte differentiation	1
dendritic cell differentiation	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
immune response	1
defense response to symbiont	1
negative regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
response to osmotic stress	1
cellular response to chemical stress	1
cellular response to abiotic stimulus	1
regulation of RNA biosynthetic process	1
gene expression	1
macromolecule biosynthetic process	1
negative regulation of biosynthetic process	1
negative regulation of macromolecule metabolic process	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
biological_process	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

3849 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RELB	NFKB2	Q00653	988
RELB	NFKB1	P19838	987
RELB	NFKBIB	Q15653	986
RELB	RELA	Q04206	985
RELB	REL	Q04864	985
RELB	NFKBIA	P25963	964
RELB	NFKBIE	O00221	937
RELB	CHUK	O15111	934
RELB	CD40	P25942	926
RELB	BCL3	P20749	882
RELB	IKBKB	O14920	878
RELB	LTBR	P36941	867
RELB	IKBKG	Q9Y6K9	831
RELB	NFKBIZ	Q9BYH8	806
RELB	LTB	P78370	800

IntAct

114 interactions, top by confidence:

A	B	Type	Score
RELB	NFKB1	psi-mi:“MI:0915”(physical association)	0.860
NFKB2	NFKB1	psi-mi:“MI:0914”(association)	0.820
RELA	NFKB1	psi-mi:“MI:0914”(association)	0.790
NFKB1	IKBKB	psi-mi:“MI:0914”(association)	0.770
RELA	RELB	psi-mi:“MI:2364”(proximity)	0.710
RELB	NFKBIE	psi-mi:“MI:0914”(association)	0.670
NFKBIA	POLRMT	psi-mi:“MI:0914”(association)	0.670
RELA	NFKBIE	psi-mi:“MI:0914”(association)	0.620
NFKB1	NFKBIE	psi-mi:“MI:2364”(proximity)	0.600
RELB	GSK3B	psi-mi:“MI:0217”(phosphorylation reaction)	0.540
GSK3B	RELB	psi-mi:“MI:0217”(phosphorylation reaction)	0.540
RELB	GSK3B	psi-mi:“MI:0915”(physical association)	0.540
GSK3B	RELB	psi-mi:“MI:0915”(physical association)	0.540
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
COMMD1	RELB	psi-mi:“MI:0915”(physical association)	0.500
MAP1LC3A	RELB	psi-mi:“MI:0407”(direct interaction)	0.440
	RELB	psi-mi:“MI:0915”(physical association)	0.400
SIX2	RELB	psi-mi:“MI:0915”(physical association)	0.400
RELB	CDK1	psi-mi:“MI:0915”(physical association)	0.370
RELB	CTSL	psi-mi:“MI:0915”(physical association)	0.370
RELB	MT1M	psi-mi:“MI:0915”(physical association)	0.370
MTAP	RELB	psi-mi:“MI:0915”(physical association)	0.370
UQCRFS1	RELB	psi-mi:“MI:0915”(physical association)	0.370
RELB	BUD31	psi-mi:“MI:0915”(physical association)	0.370
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
COMMD1	NFKB1	psi-mi:“MI:0914”(association)	0.350

BioGRID (140): RELB (Affinity Capture-MS), RELB (Affinity Capture-MS), RELB (Affinity Capture-MS), RELA (Co-localization), RELB (Co-localization), RELB (Affinity Capture-MS), REL (Affinity Capture-MS), NFKB2 (Affinity Capture-MS), RELA (Affinity Capture-MS), NFKB1 (Affinity Capture-MS), NFKBIE (Affinity Capture-MS), TNIP2 (Affinity Capture-MS), CTBS (Affinity Capture-MS), SMARCD2 (Affinity Capture-MS), SMARCD1 (Affinity Capture-MS)

ESM2 similar proteins: A2AKB9, A2AWP8, A4FV57, D3YYI7, G3V9M2, O09112, O43189, O60347, O77638, O94827, O95644, P20749, P22681, P22682, P30291, P49797, P98201, Q01201, Q04863, Q09YL6, Q0GA42, Q13202, Q13387, Q3TZ87, Q3UR85, Q3V1H9, Q5XI70, Q66T02, Q6A039, Q6RFZ7, Q6ZN18, Q70EL4, Q7Z6J2, Q86YJ5, Q8BUM9, Q8CE64, Q8N554, Q8N6N2, Q8R4T5, Q8TC41

Diamond homologs: O73630, P01125, P01126, P15307, P15330, P16236, P19838, P20749, P25799, P51509, P51510, P98149, P98150, P98152, Q00653, Q01201, Q03017, Q04206, Q04207, Q04861, Q04863, Q04864, Q04865, Q08353, Q5ZXN6, Q63369, Q6F3J0, Q7TQN4, Q91974, Q94527, Q9WTK5, A2ARS0, C9JTQ0, L7XCU0, L7XDS4, O00221, O54910, O75762, O89019, P07207

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NFKB2	“up-regulates activity”	RELB	binding
RELB	up-regulates	B_cell_maturation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of the embryonic stem cell BAF (esBAF) complex	10	69.9×	1e-14
Formation of the canonical BAF (cBAF) complex	9	66.4×	4e-13
Formation of the polybromo-BAF (pBAF) complex	9	66.4×	4e-13
RIP-mediated NFkB activation via ZBP1	8	62.5×	2e-11
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	11	58.4×	7e-15
Formation of the non-canonical BAF (ncBAF) complex	7	54.7×	1e-09
Regulation of endogenous retroelements	10	42.8×	2e-12
TRAF6 mediated NF-kB activation	8	42.5×	5e-10

GO biological processes:

GO term	Partners	Fold	FDR
regulation of G0 to G1 transition	11	86.2×	1e-16
regulation of nucleotide-excision repair	11	77.0×	3e-16
nucleosome disassembly	7	65.3×	7e-10
regulation of mitotic metaphase/anaphase transition	11	63.4×	2e-15
non-canonical NF-kappaB signal transduction	6	58.8×	4e-08
positive regulation of T cell differentiation	9	47.7×	2e-11
positive regulation of double-strand break repair	11	44.0×	2e-13
regulation of G1/S transition of mitotic cell cycle	11	39.2×	5e-13

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	245
Likely benign	224
Benign	11

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
4086100	P346L	Pathogenic
4086101	Q72TFSTER152	Pathogenic
4086102	E145K	Pathogenic
430895	NM_006509.4(RELB):c.1191C>A (p.Tyr397Ter)	Pathogenic
872128	NM_006509.4(RELB):c.662+1G>T	Likely pathogenic

SpliceAI

1883 predictions. Top by Δscore:

Variant	Effect	Δscore
19:45001683:TAG:T	donor_gain	1.0000
19:45001684:AGGT:A	donor_loss	1.0000
19:45001685:GGT:G	donor_loss	1.0000
19:45001686:GTAA:G	donor_loss	1.0000
19:45002947:AG:A	acceptor_gain	1.0000
19:45002948:GG:G	acceptor_gain	1.0000
19:45011934:A:AG	acceptor_gain	1.0000
19:45011935:G:GG	acceptor_gain	1.0000
19:45011935:GA:G	acceptor_gain	1.0000
19:45011935:GAGA:G	acceptor_gain	1.0000
19:45012273:CGAGG:C	donor_loss	1.0000
19:45012275:AG:A	donor_loss	1.0000
19:45012276:GGT:G	donor_loss	1.0000
19:45012277:GT:G	donor_loss	1.0000
19:45012278:T:A	donor_loss	1.0000
19:45025315:C:A	acceptor_gain	1.0000
19:45025319:A:AG	acceptor_gain	1.0000
19:45025320:C:G	acceptor_gain	1.0000
19:45025324:CTCA:C	acceptor_loss	1.0000
19:45025325:TCAG:T	acceptor_loss	1.0000
19:45025326:CAG:C	acceptor_loss	1.0000
19:45025327:A:AG	acceptor_gain	1.0000
19:45025327:AGTTT:A	acceptor_loss	1.0000
19:45025328:G:GG	acceptor_gain	1.0000
19:45025328:GT:G	acceptor_gain	1.0000
19:45025328:GTT:G	acceptor_gain	1.0000
19:45025328:GTTT:G	acceptor_gain	1.0000
19:45025328:GTTTT:G	acceptor_gain	1.0000
19:45025600:C:A	acceptor_gain	1.0000
19:45025602:ACAGC:A	acceptor_loss	1.0000

AlphaMissense

3728 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:45012169:C:T	P133S	1.000
19:45012170:C:A	P133H	1.000
19:45012178:C:A	R136S	1.000
19:45012181:G:C	G137R	1.000
19:45012185:T:C	M138T	1.000
19:45012185:T:G	M138R	1.000
19:45012187:C:A	R139S	1.000
19:45012187:C:G	R139G	1.000
19:45012187:C:T	R139C	1.000
19:45012188:G:A	R139H	1.000
19:45012188:G:T	R139L	1.000
19:45012190:T:A	F140I	1.000
19:45012190:T:C	F140L	1.000
19:45012190:T:G	F140V	1.000
19:45012191:T:C	F140S	1.000
19:45012191:T:G	F140C	1.000
19:45012192:C:A	F140L	1.000
19:45012192:C:G	F140L	1.000
19:45012193:C:A	R141S	1.000
19:45012193:C:G	R141G	1.000
19:45012193:C:T	R141C	1.000
19:45012194:G:A	R141H	1.000
19:45012194:G:C	R141P	1.000
19:45012194:G:T	R141L	1.000
19:45012196:T:A	Y142N	1.000
19:45012196:T:C	Y142H	1.000
19:45012196:T:G	Y142D	1.000
19:45012197:A:C	Y142S	1.000
19:45012197:A:G	Y142C	1.000
19:45012202:T:C	C144R	1.000

dbSNP variants (sampled 300 via entrez): RS1000129253 (19:45035785 C>T), RS1000212702 (19:45004571 G>A), RS1000215506 (19:45006703 G>A), RS1000265513 (19:45036233 C>T), RS1000372268 (19:45009986 C>T), RS1000441941 (19:45010990 G>A), RS1000516408 (19:45015586 T>A,C), RS1000568975 (19:45037644 G>A), RS1000926076 (19:45027335 A>C,G), RS1001009397 (19:45031752 A>G), RS1001116444 (19:45008221 A>G), RS1001219423 (19:45024457 C>A,T), RS1001300944 (19:45027694 T>A), RS1001303360 (19:45030806 T>C), RS1001346314 (19:45035289 C>T)

Disease associations

OMIM: gene MIM:604758 | disease phenotypes: MIM:617585

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 53	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 53	Limited	AR

Mondo (1): immunodeficiency 53 (MONDO:0054696)

Orphanet (1): Combined immunodeficiency due to RELB deficiency (Orphanet:688594)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000403	Recurrent otitis media
HP:0000988	Skin rash
HP:0001508	Failure to thrive
HP:0002099	Asthma
HP:0002788	Recurrent upper respiratory tract infections
HP:0003347	Impaired lymphocyte transformation with phytohemagglutinin
HP:0003593	Infantile onset
HP:0006532	Recurrent pneumonia
HP:0011897	Increased total neutrophil count
HP:0034315	Chronic cough

GWAS associations

29 associations (top):

Study	Trait	p-value
GCST005950_15	Body mass index x sex x age interaction (4df test)	2.000000e-10
GCST005951_56	Body mass index	1.000000e-06
GCST005952_8	Body mass index (age>50)	9.000000e-12
GCST005954_4	Body mass index x age interaction	2.000000e-07
GCST006993_15	Hippocampal volume in Alzheimer’s disease dementia	8.000000e-07
GCST006996_4	Cerebrospinal AB1-42 levels in mild cognitive impairment	6.000000e-27
GCST006997_3	Cerebrospinal fluid t-tau levels in mild cognitive impairment	1.000000e-13
GCST006998_7	Cerebrospinal fluid p-tau levels in mild cognitive impairment	2.000000e-11
GCST007001_15	Cerebrospinal AB1-42 levels in normal cognition	9.000000e-11
GCST007007_4	Cerebrospinal fluid t-tau levels	1.000000e-20
GCST007008_6	Cerebrospinal fluid p-tau levels	3.000000e-18
GCST007009_7	Hippocampal volume	2.000000e-19
GCST007010_3	Logical memory (delayed recall)	2.000000e-18
GCST007011_3	Logical memory (immediate recall)	2.000000e-13
GCST007012_6	Cerebrospinal fluid AB1-42 levels	1.000000e-51
GCST007320_23	Alzheimer’s disease or family history of Alzheimer’s disease	9.000000e-22
GCST007320_42	Alzheimer’s disease or family history of Alzheimer’s disease	8.000000e-13
GCST007827_13	Alzheimer’s disease or HDL levels (pleiotropy)	7.000000e-22
GCST007827_3	Alzheimer’s disease or HDL levels (pleiotropy)	1.000000e-97
GCST007827_5	Alzheimer’s disease or HDL levels (pleiotropy)	7.000000e-74
GCST007827_6	Alzheimer’s disease or HDL levels (pleiotropy)	7.000000e-54
GCST007827_7	Alzheimer’s disease or HDL levels (pleiotropy)	5.000000e-50
GCST007827_8	Alzheimer’s disease or HDL levels (pleiotropy)	3.000000e-36
GCST009738_3	Carotid intima media thickness (maximum)	7.000000e-14
GCST009921_11	Carotid intima media thickness (mean)	4.000000e-10
GCST009921_8	Carotid intima media thickness (mean)	6.000000e-15
GCST010173_3	Triglyceride levels	1.000000e-195
GCST012481_14	Cerebral amyloid angiopathy in Alzheimer’s disease	7.000000e-07
GCST90002404_535	Red cell distribution width	3.000000e-09

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0005035	hippocampal volume
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004760	t-tau measurement
EFO:0004763	p-tau measurement
EFO:0004874	memory performance
EFO:0009268	family history of Alzheimer’s disease
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523273 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — NF-kappa B TF proteins

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment, affects localization, increases activity (+3 more)	6
Benzo(a)pyrene	affects methylation, increases expression	5
Arsenic Trioxide	decreases reaction, increases expression, decreases expression	4
Tetrachlorodibenzodioxin	increases reaction, affects reaction, increases expression, affects binding, decreases reaction	4
sodium arsenite	decreases methylation, increases expression	3
Benzene	increases expression	3
Oxygen	decreases reaction, increases expression, affects cotreatment, decreases expression	3
Ozone	affects cotreatment, increases expression, decreases expression, decreases reaction	3
Silicon Dioxide	increases expression	3
nickel chloride	increases expression	2
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, affects response to substance	2
Resveratrol	decreases reaction, increases expression	2
Atrazine	affects cotreatment, increases expression	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Estradiol	increases expression	2
Methotrexate	increases expression, decreases expression	2
Nickel	increases expression	2
Plant Extracts	decreases reaction, increases expression	2
Quercetin	increases expression, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Toluene	increases expression	2
Valproic Acid	affects cotreatment, decreases expression	2
Cyclosporine	increases expression	2
Particulate Matter	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
2-anisidine	decreases expression	1
ethylbenzene	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
deoxynivalenol	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4414021	Binding	Inhibition of NF-kappaB in human JJN-3 cells assessed as reduction in RelB DNA binding activity up to 30 nM after 4 hrs by ELISA	Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs). — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2DM	Abcam HeLa RELB KO	Cancer cell line	Female
CVCL_D7ZD	Ubigene A-549 RELB KO	Cancer cell line	Male
CVCL_E0MP	Ubigene HeLa RELB KO	Cancer cell line	Female
CVCL_TI78	HAP1 RELB (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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