GPR15LG

Summary

GPR15LG (G protein-coupled receptor 15 ligand, HGNC:31428) is a protein-coding gene on chromosome 10q23.1, encoding Protein GPR15LG (Q6UWK7). Highly cationic protein that has multiple functions.

Enables chemokine activity. Involved in several processes, including defense response to other organism; mast cell degranulation; and negative regulation of cell cycle G1/S phase transition. Located in extracellular region.

Source: NCBI Gene 387695 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 4 total
• MANE Select transcript: NM_207373

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31428
Approved symbol	GPR15LG
Name	G protein-coupled receptor 15 ligand
Location	10q23.1
Locus type	gene with protein product
Status	Approved
Aliases	UNQ1833, RLLV1833, FLJ21763, CSBF, AP-57, GPR15L
Ensembl gene	ENSG00000188373
Ensembl biotype	protein_coding
OMIM	617775
Entrez	387695

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000372126, ENST00000472542

RefSeq mRNA: 1 — MANE Select: NM_207373 NM_207373

CCDS: CCDS7371

Canonical transcript exons

ENST00000372126 — 3 exons

Exon	Start	End
ENSE00001376500	84176480	84176569
ENSE00001456956	84184681	84185294
ENSE00001456958	84173801	84173921

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 99.62.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.0029 / max 2253.7782, expressed in 100 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105927	3.9602	99
105926	0.0427	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	99.62	gold quality
mucosa of transverse colon	UBERON:0004991	99.54	gold quality
gingiva	UBERON:0001828	99.53	gold quality
ileal mucosa	UBERON:0000331	99.33	gold quality
rectum	UBERON:0001052	99.07	gold quality
colonic mucosa	UBERON:0000317	99.06	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.87	gold quality
esophagus mucosa	UBERON:0002469	97.23	gold quality
pharyngeal mucosa	UBERON:0000355	97.00	gold quality
penis	UBERON:0000989	96.94	gold quality
esophagus squamous epithelium	UBERON:0006920	95.88	gold quality
lower esophagus mucosa	UBERON:0035834	95.40	gold quality
oral cavity	UBERON:0000167	93.09	gold quality
mammalian vulva	UBERON:0000997	93.07	gold quality
body of tongue	UBERON:0011876	91.00	gold quality
transverse colon	UBERON:0001157	90.91	gold quality
skin of leg	UBERON:0001511	87.36	gold quality
caecum	UBERON:0001153	85.72	gold quality
vagina	UBERON:0000996	85.63	gold quality
tongue	UBERON:0001723	85.60	gold quality
vermiform appendix	UBERON:0001154	85.09	gold quality
urinary bladder	UBERON:0001255	81.99	gold quality
zone of skin	UBERON:0000014	81.74	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.48	gold quality
colonic epithelium	UBERON:0000397	81.46	gold quality
skin of abdomen	UBERON:0001416	79.50	gold quality
large intestine	UBERON:0000059	79.13	gold quality
superior surface of tongue	UBERON:0007371	78.49	gold quality
colon	UBERON:0001155	78.23	gold quality
intestine	UBERON:0000160	77.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	924.65
E-MTAB-8410	yes	559.62
E-GEOD-125970	yes	44.25
E-ANND-3	yes	14.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting GPR15LG, 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-765	99.84	68.24	2442
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-3929	98.32	65.58	1026
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-4660	97.79	67.44	1328
HSA-MIR-3144-5P	97.64	65.45	646
HSA-MIR-6069	97.45	65.88	357
HSA-MIR-4535	97.27	65.17	469
HSA-MIR-4288	97.11	67.23	1636
HSA-MIR-632	96.08	67.17	798
HSA-MIR-764	94.16	64.85	656
HSA-MIR-492	94.02	64.46	413

Literature-anchored findings (GeneRIF, showing 3)

• Compared with other antimicrobial peptides, AP-57 has its distinct characteristics, including longer sequence length, four cysteines, highly cationic character, cell-specific toxicity, DNA binding and tissue-specific expressing patterns. (PMID:25585381)
• Results indicate that chromosome 10 open reading frame 99 protein (C10orf99) plays a contributive role in psoriasis pathogenesis and may serve as a new target for psoriasis treatment. (PMID:29872130)
• GPR15LG regulates psoriasis-like inflammation by down-regulating inflammatory factors on keratinocytes. (PMID:38393364)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gpr15lg	ENSMUSG00000096001
rattus_norvegicus	Gpr15lg	ENSRNOG00000043342

Protein

Protein identifiers

Protein GPR15LG — Q6UWK7 (reviewed: Q6UWK7)

Alternative names: Antimicrobial peptide with 57 amino acid residues, Colon-derived SUSD2 binding factor, Protein GPR15 ligand, Protein GPR15L, Secreted protein C10orf99

All UniProt accessions (1): Q6UWK7

UniProt curated annotations — full annotation on UniProt →

Function. Highly cationic protein that has multiple functions. Acts as a chemotactic factor that mediates lymphocytes recruitment to epithelia through binding and activation of the G-protein coupled receptor GPR15. May be a tumor suppressor; together with SUSD2 has a growth inhibitory effect on colon cancer cells which includes G1 cell cycle arrest. May regulate keratinocyte proliferation. In addition, through activation of Mas-related G protein-coupled receptors (MRGPRs) contributes to pruritogenesis by activating itch-selective sensory neurons and mast cells degranulation. Has antimicrobial activity against Gram-positive bacteria, including Staphylococcus aureus and Actinomyces spec., and Mycoplasma hominis and lentivirus.

Subunit / interactions. Interacts with SUSD2; the interaction is direct.

Subcellular location. Secreted.

Tissue specificity. Expressed at high levels in colon, and cervix and at moderate level in tonsil. Highly reduced expression in primary colon cancer tissues compared with that in adjacent tissues. Highest levels of expression detected in stomach and colon; expressed in epithelium of skin and esophagus, and in some tumor and/or tumor adjacent tissues (TAT), including TAT of esophagus cancer, hepatocellular carcinoma (HCC), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and invasive ductal carcinoma (IDC) tissues (at protein level). Highly expressed by inflammatory differentiated keratinocytese.

Induction. Up-regulated in the skin of psoriasis and atopic dermatitis patients.

RefSeq proteins (1): NP_997256* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031713	GPR15L	Family

Pfam: PF15854

UniProt features (6 total): disulfide bond 2, signal peptide 1, chain 1, glycosylation site 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8ZQE	ELECTRON MICROSCOPY	2.9
9WXM	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UWK7-F1	68.65	0.17

Antibody-complex structures (SAbDab): 2 — 8ZQE, 9WXM

Functional residue map

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

Disulfide bonds (2): 40–63, 41–60

Glycosylation sites (1): 48

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 106 (showing top): GOBP_CELL_CHEMOTAXIS, GOBP_NEGATIVE_REGULATION_OF_CELL_DIVISION, GOBP_KERATINOCYTE_PROLIFERATION, GOBP_T_CELL_HOMEOSTASIS, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_CELL_CYCLE_PHASE_TRANSITION, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, WOTTON_RUNX_TARGETS_UP, GOBP_LEUKOCYTE_CHEMOTAXIS

GO Biological Process (15): G protein-coupled receptor signaling pathway (GO:0007186), regulation of keratinocyte proliferation (GO:0010837), T cell homeostasis (GO:0043029), mast cell degranulation (GO:0043303), lymphocyte chemotaxis (GO:0048247), defense response to Gram-positive bacterium (GO:0050830), defense response to fungus (GO:0050832), negative regulation of cell division (GO:0051782), T cell migration (GO:0072678), negative regulation of cell cycle G1/S phase transition (GO:1902807), regulation of T cell migration (GO:2000404), chemotaxis (GO:0006935), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), defense response to bacterium (GO:0042742)

GO Molecular Function (5): G protein-coupled receptor binding (GO:0001664), chemokine activity (GO:0008009), receptor ligand activity (GO:0048018), cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
lymphocyte migration	2
defense response	2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	2
signaling receptor binding	2
G protein-coupled receptor activity	1
keratinocyte proliferation	1
regulation of epithelial cell proliferation	1
lymphocyte homeostasis	1
mast cell activation involved in immune response	1
mast cell mediated immunity	1
lysosome localization	1
leukocyte degranulation	1
establishment of organelle localization	1
leukocyte chemotaxis	1
defense response to bacterium	1
response to fungus	1
negative regulation of cellular process	1
cell division	1
regulation of cell division	1
cell cycle G1/S phase transition	1
negative regulation of cell cycle phase transition	1
regulation of cell cycle G1/S phase transition	1
T cell migration	1
regulation of lymphocyte migration	1
response to chemical	1
taxis	1
adenylate cyclase activator activity	1
adenylate cyclase inhibitor activity	1
response to bacterium	1
cytokine activity	1
chemokine receptor binding	1
cell chemotaxis	1
signaling receptor activator activity	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

274 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR15LG	GPR15	P49685	776
GPR15LG	SUSD2	Q9UGT4	742
GPR15LG	LRIT2	A6NDA9	571
GPR15LG	IGFL1	Q6UW32	469
GPR15LG	MT-ND6	P03923	447
GPR15LG	APLNR	P35414	444
GPR15LG	MT-ND4	P03905	418
GPR15LG	MT-CO1	P00395	400
GPR15LG	MT-CYB	P00156	400
GPR15LG	LRIT1	Q9P2V4	399
GPR15LG	MT-ATP8	P03928	396
GPR15LG	MT-ND3	P03897	394
GPR15LG	IL36G	Q9NZH8	381
GPR15LG	MT-CO3	P00414	376
GPR15LG	MT-ND4L	P03901	375

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A0B4J1N3, A0A1B0GTK4, A0A1B0GTR0, A0JNL8, A2RUT3, A4IFR0, C9JUS6, D3ZKM3, E9PXB6, F2Z3F1, O70899, O71302, O93195, O95411, P03165, P04610, P0C7M3, P12912, P13206, P20976, P20977, P29560, P47939, P47940, P69714, Q02919, Q08648, Q1RN00, Q1WG82, Q5PR19, Q66669, Q67923, Q69027, Q69604, Q6PDA7, Q6UWK7, Q80IU5, Q80IU8, Q8N5N4, Q913A9

Diamond homologs: A0A0B4J1N3, D3ZKM3, I3LGZ3, Q6UWK7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

477 predictions. Top by Δscore:

Variant	Effect	Δscore
10:84173919:AAG:A	donor_loss	0.9900
10:84173920:AGG:A	donor_loss	0.9900
10:84173921:GGT:G	donor_loss	0.9900
10:84173923:T:A	donor_loss	0.9900
10:84176467:T:TA	acceptor_gain	0.9900
10:84176472:A:AG	acceptor_gain	0.9900
10:84176473:C:G	acceptor_gain	0.9900
10:84176478:AG:A	acceptor_gain	0.9900
10:84176479:GG:G	acceptor_gain	0.9900
10:84176565:GAAAG:G	donor_gain	0.9900
10:84184614:A:AG	acceptor_gain	0.9900
10:84184615:C:G	acceptor_gain	0.9900
10:84184616:A:AG	acceptor_gain	0.9900
10:84184616:AACCT:A	acceptor_gain	0.9900
10:84184617:A:G	acceptor_gain	0.9900
10:84173918:GAAG:G	donor_gain	0.9800
10:84176465:T:TA	acceptor_gain	0.9800
10:84176475:CTCAG:C	acceptor_loss	0.9800
10:84176476:TCA:T	acceptor_loss	0.9800
10:84176477:CA:C	acceptor_loss	0.9800
10:84176478:A:AG	acceptor_gain	0.9800
10:84176479:G:GC	acceptor_loss	0.9800
10:84176479:G:GG	acceptor_gain	0.9800
10:84176479:GGGAA:G	acceptor_gain	0.9800
10:84176567:AAGGT:A	donor_loss	0.9800
10:84176569:GGT:G	donor_loss	0.9800
10:84176570:G:GG	donor_gain	0.9800
10:84176570:GT:G	donor_loss	0.9800
10:84176571:T:A	donor_loss	0.9800
10:84184620:T:TA	acceptor_gain	0.9700

AlphaMissense

511 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:84184736:G:C	W72C	0.987
10:84184736:G:T	W72C	0.987
10:84184753:T:A	L78H	0.981
10:84184698:T:A	C60S	0.979
10:84184699:G:C	C60S	0.979
10:84173897:T:C	C16R	0.976
10:84184746:G:A	G76R	0.976
10:84184746:G:C	G76R	0.976
10:84184747:G:T	G76V	0.975
10:84184746:G:T	G76W	0.974
10:84184747:G:A	G76E	0.973
10:84184698:T:C	C60R	0.968
10:84184699:G:A	C60Y	0.967
10:84173882:T:C	C11R	0.961
10:84184753:T:C	L78P	0.961
10:84184707:T:A	C63S	0.960
10:84184708:G:C	C63S	0.960
10:84184755:C:A	P79T	0.955
10:84184708:G:A	C63Y	0.954
10:84184699:G:T	C60F	0.952
10:84184700:T:G	C60W	0.952
10:84184744:C:A	P75H	0.951
10:84184709:C:G	C63W	0.948
10:84184755:C:T	P79S	0.947
10:84184756:C:A	P79Q	0.946
10:84176527:T:A	C40S	0.942
10:84176528:G:C	C40S	0.942
10:84176530:T:A	C41S	0.942
10:84176531:G:C	C41S	0.942
10:84176530:T:C	C41R	0.939

dbSNP variants (sampled 300 via entrez): RS1000079384 (10:84174180 A>G), RS1000456378 (10:84173063 C>T), RS1000619845 (10:84174477 G>A), RS1000830441 (10:84178125 C>A,T), RS1000938719 (10:84182886 G>A,T), RS1000999301 (10:84183465 T>A), RS1001195109 (10:84172541 G>A), RS1001215036 (10:84173262 C>T), RS1001342916 (10:84177617 C>A,T), RS1001391269 (10:84183138 G>C), RS1001442405 (10:84182538 C>T), RS1001624914 (10:84172802 C>T), RS1001861644 (10:84181779 G>T), RS1002058902 (10:84177409 C>T), RS1002186912 (10:84172276 A>G)

Disease associations

OMIM: gene MIM:617775 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_1780	Metabolite levels	6.000000e-06
GCST009391_2045	Metabolite levels	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0010457	Alpha ketoglutarate measurement
EFO:0010480	fumarate measurement
EFO:0010509	maleate measurement
EFO:0010508	malate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression	2
sodium arsenate	decreases expression, increases abundance	1
terbufos	increases methylation	1
hydroquinone	decreases expression	1
clothianidin	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Fonofos	increases methylation	1
Ethyl Methanesulfonate	increases expression	1
Parathion	increases methylation	1

Clinical trials (associated diseases)

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