XCR1

Summary

XCR1 (X-C motif chemokine receptor 1, HGNC:1625) is a protein-coding gene on chromosome 3p21.31, encoding Chemokine XC receptor 1 (P46094). Receptor for chemokines SCYC1 and SCYC2.

The protein encoded by this gene is a chemokine receptor belonging to the G protein-coupled receptor superfamily. The family members are characterized by the presence of 7 transmembrane domains. The encoded protein transduces a signal by increasing the intracellular calcium ion level. The viral macrophage inflammatory protein-II is an antagonist of this receptor and blocks signaling. Some studies have implicated a cluster of genes at 3p21.31, including this gene, as associated with COVID-19 risk. The encoded protein may also play a role in cell proliferation and migration in several types of cancer.

Source: NCBI Gene 2829 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 51 total
• Druggable target: yes
• MANE Select transcript: NM_001024644

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1625
Approved symbol	XCR1
Name	X-C motif chemokine receptor 1
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000173578
Ensembl biotype	protein_coding
OMIM	600552
Entrez	2829

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000309285, ENST00000395946, ENST00000683768

RefSeq mRNA: 3 — MANE Select: NM_001024644 NM_001024644, NM_001381860, NM_005283

CCDS: CCDS2736

Canonical transcript exons

ENST00000309285 — 2 exons

Exon	Start	End
ENSE00001209142	46017007	46021978
ENSE00001877325	46027417	46027483

Expression profiles

Bgee: expression breadth ubiquitous, 121 present calls, max score 91.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5009 / max 76.9591, expressed in 129 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41928	0.3178	66
41924	0.0555	26
41925	0.0505	26
41927	0.0386	14
41929	0.0358	11
41926	0.0027	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.45	gold quality
lymph node	UBERON:0000029	73.18	gold quality
vermiform appendix	UBERON:0001154	70.50	gold quality
pancreatic ductal cell	CL:0002079	65.97	silver quality
gall bladder	UBERON:0002110	64.22	gold quality
caecum	UBERON:0001153	63.97	gold quality
skin of leg	UBERON:0001511	63.58	gold quality
skin of abdomen	UBERON:0001416	63.47	gold quality
bone marrow cell	CL:0002092	61.59	silver quality
decidua	UBERON:0002450	60.94	silver quality
zone of skin	UBERON:0000014	60.92	gold quality
lower esophagus mucosa	UBERON:0035834	59.75	gold quality
lower lobe of lung	UBERON:0008949	59.53	silver quality
upper leg skin	UBERON:0004262	59.43	silver quality
mucosa of transverse colon	UBERON:0004991	58.67	gold quality
spleen	UBERON:0002106	58.56	gold quality
superficial temporal artery	UBERON:0001614	57.62	gold quality
rectum	UBERON:0001052	57.02	gold quality
smooth muscle tissue	UBERON:0001135	54.52	gold quality
thymus	UBERON:0002370	54.07	silver quality
colonic epithelium	UBERON:0000397	53.33	gold quality
leukocyte	CL:0000738	52.55	gold quality
duodenum	UBERON:0002114	52.13	gold quality
monocyte	CL:0000576	51.95	gold quality
mononuclear cell	CL:0000842	51.92	gold quality
placenta	UBERON:0001987	51.31	gold quality
skin of hip	UBERON:0001554	50.44	silver quality
tonsil	UBERON:0002372	50.43	gold quality
muscle tissue	UBERON:0002385	50.22	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-32	yes	268.48
E-MTAB-6678	yes	9.26
E-ANND-3	yes	3.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

2 targeting XCR1, 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-6859-3P	97.26	64.69	428
HSA-MIR-658	88.20	67.03	178

Literature-anchored findings (GeneRIF, showing 17)

• Data show that Kaposi sarcoma-associated herpes virus targets the lymphotactin receptor with both a broad spectrum antagonist vCCL2 and a highly selective and potent agonist vCCL3 (PMID:17403668)
• On the human XCR1, vCCL3 (Kaposi sarcoma- associated herpes virus), mouse XCL1 and XCL1 acted as agonists. (PMID:18426556)
• CD141+ dendritic cells are the only cells in human blood that express the chemokine receptor XCR1 and respond to the specific ligand XCL1 by Ca2+ mobilization and potent chemotaxis. (PMID:20479115)
• XCR1 constitutes the first conserved specific marker for cell subsets homologous to mouse CD8alpha+ dendritic cells in higher vertebrates. (PMID:20479118)
• The expression patterns of XCR1 and XCL1 were conserved in human and mice blood cells, including certain dendritic cell subsets. (PMID:20541533)
• XCR1 expression and biased VH gene usage are distinct features of diffuse large B-cell lymphoma initially manifesting in the bone marrow. (PMID:21411777)
• Our findings argue against the hypothesis that genetic variability in the G-Protein-Coupled Receptor Kinase 5 and Casein Kinase 2 genes modifies Parkinson disease susceptibility (PMID:21514207)
• CD8alpha-positive dendritic cells (DCs) and CD103-positive DCs belong to a common DC subset which is unequivocally identified by XCR1 transgene expression despite their different anatomical locations. (PMID:21948982)
• XCR1 is expressed early during the course of tumorigenic transformation and contributes towards increased cell migration and proliferation, which can facilitate the prometastatic behavior of epithelial ovarian cancer cells. (PMID:22964431)
• Induction of potent CD8 T cell cytotoxicity by specific targeting of antigen to cross-presenting dendritic cells in vivo via murine or human XCR1. (PMID:25520399)
• results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis (PMID:26166822)
• Demonstrate equivalence between human and mouse XCR1(+) dendritic cells and human and mouse Langerhans cells. (PMID:26966045)
• Our study provides the basis for further investigation of the molecular mechanism by which down-regulation of XCR1 promotes the development and progression of HCC. (PMID:29408492)
• XCL1-XCR1 chemokine pathway promotes trophoblast invasion by increasing matrix metalloproteinase activity in human first-trimester placenta (PMID:29856101)
• Structure-function guided modeling of chemokine-GPCR specificity for the chemokine XCL1 and its receptor XCR1. (PMID:31481523)
• Overexpression of chemokine receptor lymphotactin receptor 1 has prognostic value in clear cell renal cell carcinoma. (PMID:33377624)
• Systematic Pan-Cancer Analysis Reveals X-C Motif Chemokine Receptor 1 as a Prognostic and Immunological Biomarker. (PMID:37895310)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	xcr1b.1	ENSDARG00000052988
danio_rerio	xcr1a.1	ENSDARG00000054847
mus_musculus	Xcr1	ENSMUSG00000060509
rattus_norvegicus	Xcr1	ENSRNOG00000006620

Paralogs (23): CCR6 (ENSG00000112486), CCRL2 (ENSG00000121797), CCR2 (ENSG00000121807), CXCR4 (ENSG00000121966), CCR7 (ENSG00000126353), ACKR4 (ENSG00000129048), ACKR3 (ENSG00000144476), ACKR2 (ENSG00000144648), RGR (ENSG00000148604), CXCR5 (ENSG00000160683), CCR5 (ENSG00000160791), CXCR1 (ENSG00000163464), CCR1 (ENSG00000163823), CX3CR1 (ENSG00000168329), CXCR6 (ENSG00000172215), CCR9 (ENSG00000173585), CCR8 (ENSG00000179934), CXCR2 (ENSG00000180871), GALR2 (ENSG00000182687), CCR3 (ENSG00000183625), CCR4 (ENSG00000183813), CCR10 (ENSG00000184451), CXCR3 (ENSG00000186810)

Protein

Protein identifiers

Chemokine XC receptor 1 — P46094 (reviewed: P46094)

Alternative names: G-protein coupled receptor 5, Lymphotactin receptor, XC chemokine receptor 1

All UniProt accessions (2): P46094, Q689E2

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for chemokines SCYC1 and SCYC2. Subsequently transduces a signal by increasing the intracellular calcium ions level. Receptor for XCL1/Lymphotactin.

Subcellular location. Cell membrane.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (3): NP_001019815, NP_001368789, NP_005274 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR005393	Chemokine_XCR1	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR050119	CCR1-9-like	Family

Pfam: PF00001

UniProt features (17 total): topological domain 8, transmembrane region 7, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9AST	ELECTRON MICROSCOPY	3.07

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46094-F1	85.17	0.59

Antibody-complex structures (SAbDab): 1 — 9AST

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 (1): 102–175

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-380108	Chemokine receptors bind chemokines
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 112 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOCC_CELL_SURFACE, GOBP_MONOATOMIC_CATION_TRANSPORT, EVI1_05, GOBP_TAXIS, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_MAINTENANCE_OF_LOCATION, GOBP_MONOATOMIC_ION_HOMEOSTASIS, HAND1E47_01, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT

GO Biological Process (12): chemotaxis (GO:0006935), inflammatory response (GO:0006954), immune response (GO:0006955), G protein-coupled receptor signaling pathway (GO:0007186), G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), positive regulation of cytosolic calcium ion concentration (GO:0007204), calcium-mediated signaling (GO:0019722), release of sequestered calcium ion into cytosol (GO:0051209), cell chemotaxis (GO:0060326), signal transduction (GO:0007165), response to cytokine (GO:0034097), chemokine-mediated signaling pathway (GO:0070098)

GO Molecular Function (5): chemokine receptor activity (GO:0004950), C-C chemokine receptor activity (GO:0016493), C-C chemokine binding (GO:0019957), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide ligand-binding receptors	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	3
chemokine binding	2
response to chemical	1
taxis	1
defense response	1
immune system process	1
response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
regulation of biological quality	1
intracellular signaling cassette	1
intercellular transport	1
calcium ion transmembrane import into cytosol	1
chemotaxis	1
cell migration	1
cellular response to chemical stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
response to peptide	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
G protein-coupled chemoattractant receptor activity	1
cytokine receptor activity	1
chemokine-mediated signaling pathway	1
chemokine receptor activity	1
C-C chemokine binding	1
transmembrane signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XCR1	XCL1	P47992	999
XCR1	XCL2	Q9UBD3	997
XCR1	MPPE1	Q53F39	864
XCR1	CCL8	P78388	833
XCR1	CLEC9A	Q6UXN8	801
XCR1	GPBAR1	Q8TDU6	790
XCR1	THBD	P07204	783
XCR1	NR1H4	Q96RI1	783
XCR1	BATF3	Q9NR55	775
XCR1	CCL5	P13501	761
XCR1	CCL3	P10147	722
XCR1	ITGAE	P38570	716
XCR1	ZBTB46	Q86UZ6	712
XCR1	SIRPA	P78324	699
XCR1	LZTFL1	Q9NQ48	662

IntAct

4 interactions, top by confidence:

A	B	Type	Score
XCR1	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.560
XCR1	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): XCR1 (Affinity Capture-MS), PLEKHF2 (Two-hybrid), XCR1 (Protein-peptide), XCR1 (Proximity Label-MS)

ESM2 similar proteins: A7YY44, B0UXR0, B2GV46, E7FEL0, F8VQN3, O00398, O00590, O08707, O09027, O14843, O15529, O15552, O46685, P21556, P25105, P46002, P46093, P46094, P50132, P56484, Q00991, Q09QM4, Q13304, Q15743, Q1JQB3, Q3U507, Q3UFD7, Q3UJF0, Q4KLH9, Q6NS65, Q76EI6, Q86VZ1, Q8BFQ3, Q8BFU7, Q8BUD0, Q8BYC4, Q8C131, Q8TDS4, Q8TDS5, Q8VCK6

Diamond homologs: A6QNL7, F5HF62, O00590, O08556, O08707, O09027, O18793, O54689, O54814, O55193, O62743, O97571, O97665, O97878, O97879, O97880, O97881, O97882, O97883, O97962, O97975, P21109, P25025, P32246, P35344, P35411, P41597, P46094, P49238, P51675, P51676, P51677, P51678, P51679, P51680, P51681, P51682, P51683, P51684, P51685

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
XCL1	up-regulates	XCR1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

294 predictions. Top by Δscore:

Variant	Effect	Δscore
3:46021071:TG:T	donor_gain	0.9900
3:46027412:CTCA:C	donor_loss	0.9700
3:46027413:TCA:T	donor_loss	0.9700
3:46027414:CAC:C	donor_loss	0.9700
3:46027415:A:AC	donor_gain	0.9600
3:46027416:C:CC	donor_gain	0.9600
3:46020916:TGC:T	donor_gain	0.9400
3:46021013:G:A	donor_gain	0.9300
3:46027410:AACTC:A	donor_loss	0.9000
3:46027411:ACTCA:A	donor_loss	0.9000
3:46020764:T:A	donor_gain	0.8500
3:46023091:A:AC	donor_gain	0.8500
3:46027416:CCTGA:C	donor_gain	0.8300
3:46025275:ATG:A	donor_gain	0.8200
3:46027492:TGAAA:T	donor_gain	0.8200
3:46023318:TCA:T	donor_gain	0.8000
3:46027428:CCTCT:C	donor_gain	0.8000
3:46025277:G:A	donor_gain	0.7900
3:46021975:GCATC:G	acceptor_loss	0.7800
3:46021976:CAT:C	acceptor_gain	0.7800
3:46021978:TC:T	acceptor_loss	0.7800
3:46021979:C:CA	acceptor_loss	0.7800
3:46021980:T:A	acceptor_loss	0.7800
3:46021981:G:C	acceptor_loss	0.7800
3:46021984:A:C	acceptor_loss	0.7800
3:46021987:A:C	acceptor_loss	0.7800
3:46023319:CA:C	donor_gain	0.7800
3:46023320:AA:A	donor_gain	0.7800
3:46027416:CCTG:C	donor_gain	0.7700
3:46020911:C:CT	donor_gain	0.7600

AlphaMissense

2159 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:46021477:G:C	S157R	0.996
3:46021477:G:T	S157R	0.996
3:46021479:T:G	S157R	0.996
3:46021603:G:C	S115R	0.993
3:46021603:G:T	S115R	0.993
3:46021605:T:G	S115R	0.993
3:46021612:G:C	S112R	0.990
3:46021612:G:T	S112R	0.990
3:46021614:T:G	S112R	0.990
3:46021813:G:C	S45R	0.990
3:46021813:G:T	S45R	0.990
3:46021815:T:G	S45R	0.990
3:46021066:G:C	F294L	0.989
3:46021066:G:T	F294L	0.989
3:46021068:A:G	F294L	0.989
3:46021488:A:G	W154R	0.989
3:46021488:A:T	W154R	0.989
3:46021237:G:C	S237R	0.984
3:46021237:G:T	S237R	0.984
3:46021239:T:G	S237R	0.984
3:46021732:G:C	N72K	0.983
3:46021732:G:T	N72K	0.983
3:46021600:G:C	S116R	0.982
3:46021600:G:T	S116R	0.982
3:46021602:T:G	S116R	0.982
3:46021568:C:G	R127P	0.981
3:46021801:G:C	N49K	0.979
3:46021801:G:T	N49K	0.979
3:46021236:A:G	W238R	0.976
3:46021236:A:T	W238R	0.976

dbSNP variants (sampled 300 via entrez): RS1000017008 (3:46067345 T>A), RS1000040252 (3:46070133 A>C,G,T), RS1000118251 (3:46017731 T>G), RS1000140690 (3:46033127 G>A,C,T), RS1000165046 (3:46044478 G>T), RS1000168280 (3:46051754 C>T), RS1000171259 (3:46077102 A>G), RS1000193659 (3:46033523 G>C), RS1000302692 (3:46069634 T>C), RS1000355055 (3:46084244 G>C,T), RS1000378975 (3:46048392 A>C,T), RS1000431280 (3:46040677 C>G), RS1000479489 (3:46060772 C>A), RS1000532893 (3:46063099 G>A), RS1000606675 (3:46077377 G>A)

Disease associations

OMIM: gene MIM:600552 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST90000255_22	Severe COVID-19 infection with respiratory failure (analysis I)	1.000000e-10
GCST90000256_1	Severe COVID-19 infection with respiratory failure (analysis II)	9.000000e-12
GCST90011899_121	Aspartate aminotransferase levels	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4339 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Chemokine receptors

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
[125I]XCL1 (human)	Full agonist	8.0	pKd
XCL1	Agonist	7.3	pEC50
XCL2	Agonist	7.3	pEC50

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
Valproic Acid	increases expression, increases methylation, affects cotreatment	2
bisphenol A	decreases methylation	1
zinc chloride	decreases expression	1
ferrous sulfate	decreases expression	1
1-nitropyrene	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
lipopolysaccharide, E. coli O26-B6	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	increases expression	1
Catechin	decreases expression	1
Flavonoids	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Ozone	affects expression, increases abundance	1
Plant Extracts	increases expression	1
Silicon Dioxide	decreases expression	1
tert-Butylhydroperoxide	increases methylation	1
Particulate Matter	increases expression	1
Soot	decreases expression	1
Polyphenols	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4028342	Functional	Antagonist activity at human XCR1 expressed in CHOK1 cells assessed as inhibition of lymphotactin-induced cAMP accumulation at 10 uM preincubated for 30 mins followed agonist addition measured after 30 to 60 mins	Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KV90	cAMP Hunter CHO-K1 XCR1 Gi	Spontaneously immortalized cell line	Female
CVCL_KZ26	PathHunter CHO-K1 XCR1 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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