LTBR

Summary

LTBR (lymphotoxin beta receptor, HGNC:6718) is a protein-coding gene on chromosome 12p13.31, encoding Tumor necrosis factor receptor superfamily member 3 (P36941). Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT.

This gene encodes a member of the tumor necrosis factor receptor superfamily. The major ligands of this receptor include lymphotoxin alpha/beta and tumor necrosis factor ligand superfamily member 14. The encoded protein plays a role in signalling during the development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Activity of this receptor has also been linked to carcinogenesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed.

Source: NCBI Gene 4055 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 86 total
• Druggable target: yes
• MANE Select transcript: NM_002342

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6718
Approved symbol	LTBR
Name	lymphotoxin beta receptor
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	TNFCR, TNFR-RP, TNFR2-RP, TNF-R-III, TNFRSF3
Ensembl gene	ENSG00000111321
Ensembl biotype	protein_coding
OMIM	600979
Entrez	4055

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 17 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000228918, ENST00000440421, ENST00000441074, ENST00000444814, ENST00000535739, ENST00000536876, ENST00000539925, ENST00000541005, ENST00000541102, ENST00000542830, ENST00000543190, ENST00000543542, ENST00000544454, ENST00000545445, ENST00000546296, ENST00000884044, ENST00000884045, ENST00000884046, ENST00000884047, ENST00000957629, ENST00000957630, ENST00000957631, ENST00000957632, ENST00000957633, ENST00000957634, ENST00000957635, ENST00000957636

RefSeq mRNA: 12 — MANE Select: NM_002342 NM_001270987, NM_001414303, NM_001414304, NM_001414305, NM_001414306, NM_001414307, NM_001414308, NM_001414309, NM_001414310, NM_001414311, NM_001414312, NM_002342

CCDS: CCDS59233, CCDS8544

Canonical transcript exons

ENST00000228918 — 10 exons

Exon	Start	End
ENSE00002212537	6390660	6391566
ENSE00002313842	6384162	6384454
ENSE00003478248	6385022	6385147
ENSE00003520456	6385227	6385379
ENSE00003535658	6384588	6384684
ENSE00003539266	6388800	6388825
ENSE00003566591	6388398	6388505
ENSE00003614798	6386066	6386162
ENSE00003652266	6386347	6386444
ENSE00003687331	6390112	6390340

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 98.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.5855 / max 345.8253, expressed in 1663 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123656	52.5025	1618
123652	1.8809	1071
123655	1.2290	835
123654	1.1092	742
123650	0.7462	270
123653	0.7025	478
123659	0.4958	294
123657	0.4483	293
123658	0.3873	214
206551	0.0608	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.16	gold quality
right lobe of thyroid gland	UBERON:0001119	98.02	gold quality
left lobe of thyroid gland	UBERON:0001120	97.95	gold quality
minor salivary gland	UBERON:0001830	97.89	gold quality
body of pancreas	UBERON:0001150	97.84	gold quality
body of stomach	UBERON:0001161	97.79	gold quality
upper lobe of left lung	UBERON:0008952	97.75	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.64	gold quality
right lobe of liver	UBERON:0001114	97.56	gold quality
metanephros cortex	UBERON:0010533	97.55	gold quality
left uterine tube	UBERON:0001303	97.49	gold quality
skin of abdomen	UBERON:0001416	97.47	gold quality
transverse colon	UBERON:0001157	97.46	gold quality
ectocervix	UBERON:0012249	97.42	gold quality
esophagus mucosa	UBERON:0002469	97.39	gold quality
mucosa of stomach	UBERON:0001199	97.34	gold quality
gall bladder	UBERON:0002110	97.32	gold quality
body of uterus	UBERON:0009853	97.32	gold quality
lower esophagus	UBERON:0013473	97.30	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.29	gold quality
esophagus	UBERON:0001043	97.27	gold quality
right lung	UBERON:0002167	97.22	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.20	gold quality
skin of leg	UBERON:0001511	97.19	gold quality
right coronary artery	UBERON:0001625	97.19	gold quality
endocervix	UBERON:0000458	97.15	gold quality
mucosa of transverse colon	UBERON:0004991	97.15	gold quality
left adrenal gland	UBERON:0001234	97.08	gold quality
left adrenal gland cortex	UBERON:0035825	97.03	gold quality
thyroid gland	UBERON:0002046	96.91	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-81608	no	7.87
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, NFKB, NR3C1, WWTR1

miRNA regulators (miRDB)

29 targeting LTBR, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-1199-5P	98.44	66.51	829
HSA-MIR-6751-3P	98.44	66.35	835
HSA-MIR-5088-5P	97.97	64.28	487
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-1182	96.41	64.89	336
HSA-MIR-4264	96.35	64.76	1480
HSA-MIR-4640-3P	94.58	63.02	263
HSA-MIR-662	90.64	62.72	148

Literature-anchored findings (GeneRIF, showing 40)

• Lymphotoxin beta receptor induces interleukin 8 gene expression via NF-kappaB and AP-1 activation.(AP-1) (PMID:12169272)
• The NF-kappa B activation in lymphotoxin beta receptor signaling depends on the phosphorylation of p65 at serine 536. (PMID:12419817)
• Data show that mRNA encoding LIGHT and its receptors [HVEM, LTbetaR, and TR6 (DcR3)] are present in placentas and cytotrophoblast cells at term. (PMID:12466117)
• ASK1 is one of the factors involved in the caspase-independent pathway of LTbetaR-induced cell death. (PMID:12566458)
• TRAF2, TRAF3, cIAP1, Smac, and lymphotoxin beta receptor associate and are involved in apoptosis (PMID:12571250)
• LTbetaR, CD40 and TANK interact with TRAF3 at sites that promote molecular interactions driving specific signaling (PMID:14517219)
• both LTbetaR and HVEM can discriminatively mediate the expression of different genes in cultured human umbilical vein endothelial cells, including LIGHT, a proinflammatory cytokine (PMID:15917993)
• Signaling through the lymphotoxin beta receptor (LTbetaR) expressed on mature hepatocytes induces massive hepatomegaly; LTbetaR and its ligands define a new pathway in supporting liver regeneration (PMID:16002734)
• Blockade of TNFSF14 signaling caused a substantial reduction in the expression of lymphotoxin beta receptor (LTbetaR)-controlled migration factors within the islets and disrupts organization of tertiary structures, leading to prevention of diabetes. (PMID:16934497)
• membrane-bound receptor that mediates apoptosis (LTbetaR) was present in syncytiotrophoblast and cytotrophoblast cells in all samples but were detected in placental stromal cells only at week 8 and thereafter (PMID:17010447)
• Evidence in this review indicates that double positive-thymocytes regulate the differentiation of early thymocyte progenitors and gamma delta T cells through a mechanism dependent on LT beta receptor. (PMID:17336158)
• These results define a model for the study of inflammatory lymphangiogenesis in the thyroid and implicate lymphotoxin beta receptor signaling in this process. (PMID:17360402)
• This review discusses recent studies indicating that LT beta R signaling is required for liver regeneration, hepatitis, and hepatic lipid metabolism. (PMID:17896993)
• Lymphotoxin beta receptor ligation directly activates gene expression in human vascular endothelial cells via both noncanonical and classical NF-kappa B pathways. (PMID:18292573)
• LTbeta-R constitutively induces NF-kappaB activation, and this event may be associated with autonomous growth of melanoma cells. (PMID:18347013)
• lymphotoxin beta receptor (LTbetaR) was detected in Rheumatoid arthritis fibroblast-like synoviocytes (PMID:18412315)
• Sustained LT signaling represents a pathway involved in hepatitis-induced hepatocellular carcinoma. (PMID:19800575)
• Modulation of cellular TRAF3 levels may thus contribute to regulation of NFkappaB-dependent gene expression by LTBR by affecting the balance of LTBR-dependent activation of canonical and non-canonical NFkappaB pathways. (PMID:20185819)
• the LTbetaR modifies the ubiquitin:NIK E3 ligase, and also acts as an allosteric regulator of the ubiquitin:TRAF E3 ligase (PMID:20348096)
• Increased potential for LTbeta receptor signaling, coupled with increased bioavailability due to lower decoy receptor-3 (DcR3) avidity, provides a mechanism for polymorphic variants in LIGHT to contribute to the pathogenesis of inflammatory diseases. (PMID:20592286)
• LTbetaR levels are independently associated with atherosclerosis in multiple vascular beds (PMID:20599198)
• These results indicated that AdipoR1 interacted with LTBR and mediated the inhibition of LTBR-activated NF-kappaB pathway. (PMID:21195057)
• show that a cognate interaction between LTalphabeta on CD4(+) helper T cells and LTbeta receptor on DCs results in unique signals that are necessary for optimal CD8(+) T-cell expansion via a type I IFN-dependent mechanism (PMID:21245292)
• Results suggest that blockade of lymphotoxin-beta receptor (LTBR) pathways may have therapeutic potential for treatment of Sjogren’s syndrome. (PMID:22044682)
• LTBR gene polymorphisms may be associated with risk of IgA nephropathy in Korean children (PMID:22417320)
• Studies indicate roles for Lymphotoxin-alpha (LTalpha) and lymphotoxin-beta receptor (LTbetaR) pathway in innate and adaptive immune responses to microorganisms. (PMID:23524463)
• Dimerization of LTbetaR by LTalpha1beta2 is necessary and sufficient for signal transduction. (PMID:24248355)
• lymphotoxin-B-specific receptor. (PMID:24563505)
• Relative expression of HVEM and LTbetaR modulates canonical NF-kappaB and pro-apoptotic signals stimulated by LIGHT. (PMID:24980868)
• LIGHT, via LTbetaR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells. (PMID:25501580)
• activation enhances the LPS-induced expression of IL-8 through NF-kappaB and IRF-1 (PMID:25887375)
• We found that LTbetaR polymorphisms caused severe BPH. Thus, LTbetaR may contribute to the risk of BPH development. (PMID:26782510)
• membrane-bound lymphotoxin-beta receptor (LTbetaR) and CXC chemokine receptor 2 (CXCR2), is involved in type B EAE development (PMID:27820602)
• LIGHT and LTBR interaction increases the survival and proliferation of human bone marrow-derived mesenchymal stem cells, and therefore, LIGHT might play an important role in stem cell therapy. (PMID:27835685)
• these results suggest that the LTBR rs12354 polymorphism might be associated with the spontaneous resolution of hepatitis B virus infection (PMID:28575727)
• LTBR and BCLAF1 showed higher DNA methylation percentages in the marsupialized OKCs, but this difference did not affect gene expression (P > .05). (PMID:28864293)
• the lymphotoxin beta receptor (LTbetaR) to elicit the fast release of NF-kappaB inducing kinase (NIK) from the receptor complex leading to non-canonical NF-kappaB signaling. (PMID:29329668)
• Authors found that knockdown of Rab7a or HOPS components led to sequestration of LTbetaR in intraluminal vesicles of endosomes, thus precluding NF-kappaB signaling. This was in contrast to the LTbetaR localization on the outer endosomal membrane that was seen after ESCRT depletion and was permissive for signaling. (PMID:30333141)
• These data provide the first evidence of overexpression of LIGHT and its receptors HVEM and LT beta receptor in systemic sclerosis and suggest that the LIGHT axis might contribute to the pathogenesis of systemic sclerosis. (PMID:30508197)
• The Nuclear Protein HOXB13 Enhances Methylmercury Toxicity by Inducing Oncostatin M and Promoting Its Binding to TNFR3 in Cultured Cells. (PMID:31878059)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdr	ENSDARG00000004392
danio_rerio	tnfrsfa	ENSDARG00000004451
danio_rerio	cd40	ENSDARG00000054968
danio_rerio	nradd	ENSDARG00000057143
danio_rerio	tnfrsf1b	ENSDARG00000070165
danio_rerio	tnfrsf11a	ENSDARG00000087804
mus_musculus	Ltbr	ENSMUSG00000030339
rattus_norvegicus	Ltbr	ENSRNOG00000019264

Paralogs (21): FAS (ENSG00000026103), TNFRSF1B (ENSG00000028137), TNFRSF9 (ENSG00000049249), RELT (ENSG00000054967), NGFR (ENSG00000064300), TNFRSF1A (ENSG00000067182), CD40 (ENSG00000101017), TNFRSF10A (ENSG00000104689), TNFRSF10B (ENSG00000120889), TNFRSF8 (ENSG00000120949), CD27 (ENSG00000139193), TNFRSF11A (ENSG00000141655), TNFRSF21 (ENSG00000146072), TNFRSF14 (ENSG00000157873), TNFRSF11B (ENSG00000164761), TNFRSF10D (ENSG00000173530), TNFRSF10C (ENSG00000173535), TNFRSF4 (ENSG00000186827), TNFRSF18 (ENSG00000186891), TNFRSF25 (ENSG00000215788), TNFRSF6B (ENSG00000243509)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 3 — P36941 (reviewed: P36941)

Alternative names: Lymphotoxin-beta receptor, Tumor necrosis factor C receptor, Tumor necrosis factor receptor 2-related protein, Tumor necrosis factor receptor type III

All UniProt accessions (5): P36941, F5H1S5, F5H2E7, F5H627, F5H6F8

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT. Activates NF-kappa-B signaling pathway upon stimulation with lymphotoxin (LTA(1)-LTB(2)). Promotes apoptosis via TRAF3 and TRAF5. May play a role in the development of lymphoid organs.

Subunit / interactions. Self-associates; dimerization and trimerization are promoted by lymphotoxin (LTA(1)-LTB(2)). Associates with TRAF3. Associates with TRAF4. Associates with TRAF5. Interacts with Aedes aegypti lymphotoxin beta receptor inhibitor; the interaction reduces dimerization and trimerization of LTBR induced by lymphotoxin (LTA(1)-LTB(2)). (Microbial infection) Interacts with HCV core protein.

Subcellular location. Membrane.

Isoforms (2)

UniProt ID	Names	Canonical?
P36941-1	1	yes
P36941-2	2

RefSeq proteins (12): NP_001257916, NP_001401232, NP_001401233, NP_001401234, NP_001401235, NP_001401236, NP_001401237, NP_001401238, NP_001401239, NP_001401240, NP_001401241, NP_002333* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001368	TNFR/NGFR_Cys_rich_reg	Domain
IPR017349	TNFR_3_LTBR	Family
IPR033997	TNFRSF3_N	Domain

Pfam: PF00020

UniProt features (32 total): disulfide bond 10, repeat 4, compositionally biased region 3, glycosylation site 2, topological domain 2, mutagenesis site 2, sequence conflict 2, signal peptide 1, chain 1, modified residue 1, splice variant 1, sequence variant 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1RF3	X-RAY DIFFRACTION	3.5
4MXW	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36941-F1	66.90	0.33

Antibody-complex structures (SAbDab): 1 — 4MXW

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 (1): 323

Disulfide bonds (10): 43–58, 59–72, 62–80, 83–98, 101–116, 104–124, 126–132, 139–148, 142–167, 170–185

Glycosylation sites (2): 40, 177

Mutagenesis-validated functional residues (2):

Position	Phenotype
40	does not affect interaction with aedes aegypti lymphotoxin beta receptor inhibitor.
177	does not affect interaction with a.aegypti lymphotoxin beta receptor inhibitor.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway
R-HSA-5676594	TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway

MSigDB gene sets: 236 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, MODULE_52, GOBP_DENDRITIC_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_ACTIVATION_OF_NF_KAPPAB_INDUCING_KINASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, USF_C, MODULE_70

GO Biological Process (9): apoptotic process (GO:0006915), immune response (GO:0006955), signal transduction (GO:0007165), myeloid dendritic cell differentiation (GO:0043011), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of JNK cascade (GO:0046330), hematopoietic or lymphoid organ development (GO:0048534), cellular response to mechanical stimulus (GO:0071260), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238)

GO Molecular Function (4): ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (3): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cytokine Signaling in Immune system	1
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
immune system process	1
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
myeloid dendritic cell activation	1
myeloid leukocyte differentiation	1
dendritic cell differentiation	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
immune system development	1
animal organ development	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
extrinsic apoptotic signaling pathway	1
positive regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
ubiquitin-like protein ligase binding	1
protein binding	1
signaling receptor activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1613 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LTBR	TNFSF14	O43557	998
LTBR	LTB	P78370	998
LTBR	LTA	P01374	995
LTBR	TRAF3	Q13114	945
LTBR	TNFRSF13C	Q96RJ3	937
LTBR	TNF	P01375	892
LTBR	RELB	Q01201	867
LTBR	TRAF5	O00463	863
LTBR	NFKB2	Q00653	857
LTBR	TNFSF13B	Q9Y275	819
LTBR	CHUK	O15111	812
LTBR	AIRE	O43918	768
LTBR	TNFRSF1B	P20333	741
LTBR	FASLG	P48023	738
LTBR	CCL19	Q99731	728

IntAct

43 interactions, top by confidence:

A	B	Type	Score
LTBR	TRAF2	psi-mi:“MI:0915”(physical association)	0.670
LTBR	TRAF3	psi-mi:“MI:0915”(physical association)	0.670
LTBR	TRAF2	psi-mi:“MI:0914”(association)	0.670
	LTBR	psi-mi:“MI:0915”(physical association)	0.620
LTBR		psi-mi:“MI:0915”(physical association)	0.620
	LTBR	psi-mi:“MI:0403”(colocalization)	0.620
EHHADH	LTBR	psi-mi:“MI:0915”(physical association)	0.560
LTBR	EHHADH	psi-mi:“MI:0915”(physical association)	0.560
LTBR	RABAC1	psi-mi:“MI:0915”(physical association)	0.560
LTBR		psi-mi:“MI:0915”(physical association)	0.550
LTBR	ZNF724	psi-mi:“MI:0914”(association)	0.530
TNFSF14	LTBR	psi-mi:“MI:0915”(physical association)	0.520
LTBR	TNFSF14	psi-mi:“MI:0915”(physical association)	0.520
LTBR	ZMYND11	psi-mi:“MI:0915”(physical association)	0.510
LTBR	LTBR	psi-mi:“MI:0915”(physical association)	0.510
ZMYND11	LTBR	psi-mi:“MI:0915”(physical association)	0.510
LTBR	DEAF1	psi-mi:“MI:0915”(physical association)	0.400
HES1	LTBR	psi-mi:“MI:0915”(physical association)	0.370
“BALF4	LTBR	psi-mi:“MI:0915”(physical association)	0.370
Bmpr1a	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Calml3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (235): UBB (Affinity Capture-MS), ZNF865 (Affinity Capture-MS), BLZF1 (Affinity Capture-MS), CCDC93 (Affinity Capture-MS), SPATS2 (Affinity Capture-MS), CEP131 (Affinity Capture-MS), HGS (Affinity Capture-MS), ODF2 (Affinity Capture-MS), PRC1 (Affinity Capture-MS), ZNF724P (Affinity Capture-MS), BIRC2 (Affinity Capture-MS), TAOK2 (Affinity Capture-MS), PLK1 (Affinity Capture-MS), TRAF3 (Affinity Capture-MS), ZWINT (Affinity Capture-MS)

ESM2 similar proteins: A2APT9, A5PJC7, B0BN44, O94989, O95153, P14753, P19235, P25118, P36941, P40238, Q01114, Q07303, Q13671, Q2KL21, Q3U4N7, Q3UYR4, Q400G9, Q49LS3, Q5F267, Q5FWH6, Q5GH66, Q5JXC2, Q5R866, Q6UX68, Q6ZVH7, Q7TNF8, Q7Z3H0, Q80VJ8, Q80W87, Q8BG26, Q8BX43, Q8C310, Q8CII8, Q8MII8, Q8N386, Q8NBR0, Q8TE82, Q8WZ75, Q921Q7, Q93038

Diamond homologs: A5D7R1, D3ZF92, O00300, O08712, O08727, O35305, O75509, O95407, P0DTN0, P20333, P25119, P25942, P25943, P27512, P29825, P36941, P43489, P83626, Q28203, Q3LRP1, Q3ZTK5, Q63199, Q7YRL5, Q8SQ34, Q9EPU5, Q9Y6Q6, O73559, P0DSV7, P0DSV8, P68636, P68637, P07174, P08138, P15725, P20334, P47741, P50284, Q07011, Q9Z0W1, O14763

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
LTBR	up-regulates	B_cell_maturation
LTBR	up-regulates	Lymphoma
WWTR1	“up-regulates quantity by expression”	LTBR	“transcriptional regulation”
LTA	up-regulates	LTBR	binding
LTB	“up-regulates activity”	LTBR	binding
LTBR	“up-regulates activity”	TRAF2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	7
Benign	13

Top pathogenic / likely-pathogenic (0)

SpliceAI

1351 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6384460:G:GT	donor_gain	1.0000
12:6384574:A:AG	acceptor_gain	1.0000
12:6384575:T:G	acceptor_gain	1.0000
12:6384583:T:A	acceptor_gain	1.0000
12:6384583:TGAA:T	acceptor_loss	1.0000
12:6384584:GAAG:G	acceptor_loss	1.0000
12:6384586:A:AG	acceptor_gain	1.0000
12:6384586:AG:A	acceptor_gain	1.0000
12:6384586:AGGT:A	acceptor_gain	1.0000
12:6384587:G:GT	acceptor_gain	1.0000
12:6384587:GG:G	acceptor_gain	1.0000
12:6384587:GGT:G	acceptor_gain	1.0000
12:6384587:GGTG:G	acceptor_gain	1.0000
12:6384587:GGTGC:G	acceptor_gain	1.0000
12:6384682:CAGG:C	donor_loss	1.0000
12:6384683:AG:A	donor_loss	1.0000
12:6384684:GG:G	donor_loss	1.0000
12:6384685:GT:G	donor_loss	1.0000
12:6385146:AGGTG:A	donor_loss	1.0000
12:6385147:GGTG:G	donor_loss	1.0000
12:6385148:G:GA	donor_loss	1.0000
12:6385225:A:AG	acceptor_gain	1.0000
12:6385226:G:GG	acceptor_gain	1.0000
12:6385226:GT:G	acceptor_gain	1.0000
12:6385226:GTGAT:G	acceptor_gain	1.0000
12:6386064:A:AG	acceptor_gain	1.0000
12:6386065:G:GG	acceptor_gain	1.0000
12:6386343:GCAG:G	acceptor_loss	1.0000
12:6386344:CAGG:C	acceptor_loss	1.0000
12:6386345:A:AC	acceptor_loss	1.0000

AlphaMissense

2807 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6386116:T:C	F175L	0.997
12:6386118:C:A	F175L	0.997
12:6386118:C:G	F175L	0.997
12:6386117:T:G	F175C	0.996
12:6384684:G:T	G65C	0.995
12:6385107:C:A	N93K	0.995
12:6385107:C:G	N93K	0.995
12:6385120:T:A	C98S	0.994
12:6385121:G:C	C98S	0.994
12:6386146:T:A	C185S	0.994
12:6386147:G:C	C185S	0.994
12:6384675:T:A	C62S	0.993
12:6384676:G:C	C62S	0.993
12:6385121:G:A	C98Y	0.993
12:6386101:T:A	C170S	0.993
12:6386102:G:C	C170S	0.993
12:6385022:G:T	G65V	0.992
12:6385104:G:C	W92C	0.992
12:6385104:G:T	W92C	0.992
12:6385120:T:C	C98R	0.992
12:6385122:C:G	C98W	0.992
12:6386348:T:A	C191S	0.992
12:6386349:G:C	C191S	0.992
12:6385075:T:A	C83S	0.991
12:6385076:G:C	C83S	0.991
12:6384675:T:C	C62R	0.990
12:6385139:G:A	C104Y	0.990
12:6386146:T:C	C185R	0.990
12:6384677:C:G	C62W	0.989
12:6386381:G:T	G202C	0.989

dbSNP variants (sampled 300 via entrez): RS1000134035 (12:6385821 C>A,T), RS1000148974 (12:6383327 C>G,T), RS1000182339 (12:6383061 T>C), RS1000420080 (12:6378435 G>A,T), RS1000487132 (12:6382289 C>T), RS1000518043 (12:6381991 A>C), RS1000548812 (12:6383647 T>C), RS1000645788 (12:6391042 A>G), RS1000748368 (12:6387306 T>C), RS1000813657 (12:6388605 A>G), RS1001074968 (12:6387370 T>C), RS1001435624 (12:6373369 G>A), RS1001441625 (12:6374659 G>A), RS1001485726 (12:6378900 T>G), RS1001516693 (12:6378538 G>A)

Disease associations

OMIM: gene MIM:600979 | disease phenotypes: MIM:264350, MIM:613021, MIM:618126

GenCC curated gene-disease

Mondo (3): pseudohypoaldosteronism, type IB1, autosomal recessive (MONDO:0009917), bronchiectasis with or without elevated sweat chloride 2 (MONDO:0013087), Liddle syndrome 3 (MONDO:0029132)

Orphanet (3): Generalized pseudohypoaldosteronism type 1 (Orphanet:171876), Idiopathic bronchiectasis (Orphanet:60033), Pseudohypoaldosteronism type 1 (Orphanet:756)

HPO phenotypes

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

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST003044_41	Crohn’s disease	1.000000e-09
GCST003995_1	Tonsillectomy	2.000000e-35
GCST004131_124	Inflammatory bowel disease	3.000000e-06
GCST004132_26	Crohn’s disease	5.000000e-09
GCST004607_41	Plateletcrit	3.000000e-11
GCST004608_174	Granulocyte percentage of myeloid white cells	7.000000e-27
GCST004609_190	Monocyte percentage of white cells	4.000000e-46
GCST004862_92	Itch intensity from mosquito bite adjusted by bite size	4.000000e-07
GCST004865_7	Itch intensity from mosquito bite adjusted by bite size	5.000000e-08
GCST005014_64	Tonsillectomy	2.000000e-35
GCST005528_24	Juvenile idiopathic arthritis (oligoarticular or rheumatoid factor-negative polyarticular)	5.000000e-09
GCST005529_23	Ankylosing spondylitis	8.000000e-10
GCST005529_30	Ankylosing spondylitis	1.000000e-07
GCST005529_41	Ankylosing spondylitis	3.000000e-10
GCST005531_5	Multiple sclerosis	7.000000e-14
GCST005537_86	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	3.000000e-14
GCST005581_33	Primary biliary cirrhosis	2.000000e-16
GCST005581_34	Primary biliary cirrhosis	7.000000e-19
GCST005581_7	Primary biliary cirrhosis	1.000000e-14
GCST005581_8	Primary biliary cirrhosis	2.000000e-09
GCST009066_24	Mosaic loss of chromosome Y (Y chromosome dosage)	2.000000e-18
GCST009067_19	Mosaic loss of chromosome Y (Y chromosome dosage)	4.000000e-22
GCST009597_56	Multiple sclerosis	2.000000e-20
GCST010064_3	Celiac disease	5.000000e-09
GCST90002379_98	Basophil count	8.000000e-11
GCST90002382_304	Eosinophil percentage of white cells	5.000000e-16
GCST90002393_408	Monocyte count	1.000000e-102
GCST90002394_360	Monocyte percentage of white cells	1.000000e-122
GCST90002400_72	Plateletcrit	1.000000e-25
GCST90002401_232	Platelet distribution width	1.000000e-11

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement
EFO:0007985	platelet crit
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0005090	basophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007984	platelet component distribution width
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567813	Bronchiectasis With Or Without Elevated Sweat Chloride 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1250360 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Tumour necrosis factor (TNF) receptor family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, increases expression, affects expression	3
methylmercuric chloride	affects binding, increases reaction	2
Zoledronic Acid	affects cotreatment, decreases expression, increases expression	2
Vehicle Emissions	affects cotreatment, increases expression, increases abundance	2
Particulate Matter	affects cotreatment, increases abundance, increases expression	2
2-anisidine	decreases expression	1
triphenyl phosphate	affects expression	1
VX-agent	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
arsenite	increases expression, affects reaction	1
sodium bichromate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
usnic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	decreases expression	1
K 7174	increases expression	1
lipopolysaccharide, E. coli O26-B6	decreases expression	1
3,5-bis(2-fluorobenzylidene)piperidin-4-one	decreases reaction, increases expression	1
jinfukang	increases expression, increases reaction	1
Rosiglitazone	increases expression	1
Resveratrol	decreases reaction, increases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Vorinostat	decreases expression	1
Allergens	affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation	1
Chelating Agents	affects binding, decreases expression	1
Cisplatin	increases expression, increases reaction	1
Copper	affects binding, decreases 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
CHEMBL1250030	Binding	Binding affinity to human lymphotoxin beta receptor by surface plasmon resonance method	C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L. — Nat Chem Biol

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1XG	Abcam A-549 LTBR KO	Cancer cell line	Male
CVCL_D2BQ	Abcam HCT 116 LTBR KO	Cancer cell line	Male
CVCL_D7TV	Ubigene A-549 LTBR KO	Cancer cell line	Male
CVCL_D8PI	Ubigene HCT 116 LTBR KO	Cancer cell line	Male
CVCL_E0GR	Ubigene HeLa LTBR KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases