ACKR4

gene
On this page

Also known as CCR11CCBP2VSHK1CCX-CKRPPR1

Summary

ACKR4 (atypical chemokine receptor 4, HGNC:1611) is a protein-coding gene on chromosome 3q22.1, encoding Atypical chemokine receptor 4 (Q9NPB9). Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis.

The protein encoded by this gene is a member of the G protein-coupled receptor family, and is a receptor for C-C type chemokines. This receptor has been shown to bind dendritic cell- and T cell-activated chemokines including CCL19/ELC, CCL21/SLC, and CCL25/TECK. A pseudogene of this gene is found on chromosome 6. Alternatively spliced transcript variants encoding the same protein have been described.

Source: NCBI Gene 51554 — RefSeq curated summary.

At a glance

  • GWAS associations: 5
  • Clinical variants (ClinVar): 1 total
  • MANE Select transcript: NM_016557

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:1611
Approved symbolACKR4
Nameatypical chemokine receptor 4
Location3q22.1
Locus typegene with protein product
StatusApproved
AliasesCCR11, CCBP2, VSHK1, CCX-CKR, PPR1
Ensembl geneENSG00000129048
Ensembl biotypeprotein_coding
OMIM606065
Entrez51554

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 nonsense_mediated_decay

ENST00000249887, ENST00000509820, ENST00000878670, ENST00000964709

RefSeq mRNA: 2 — MANE Select: NM_016557 NM_016557, NM_178445

CCDS: CCDS3075

Canonical transcript exons

ENST00000249887 — 2 exons

ExonStartEnd
ENSE00000885857132600389132602644
ENSE00001231496132597270132597323

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 86.15.

FANTOM5 (CAGE): breadth broad, TPM avg 4.7280 / max 270.4053, expressed in 392 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter IDTPM avgSamples expressed
386344.5240388
386330.204091

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
duodenumUBERON:000211486.15gold quality
ascending aortaUBERON:000149679.95gold quality
thoracic aortaUBERON:000151579.92gold quality
gall bladderUBERON:000211078.60gold quality
descending thoracic aortaUBERON:000234576.92gold quality
subcutaneous adipose tissueUBERON:000219076.73gold quality
right coronary arteryUBERON:000162575.96gold quality
skin of legUBERON:000151175.61gold quality
zone of skinUBERON:000001475.39gold quality
calcaneal tendonUBERON:000370175.09gold quality
skin of abdomenUBERON:000141674.88gold quality
pituitary glandUBERON:000000774.58gold quality
right atrium auricular regionUBERON:000663173.78gold quality
adipose tissueUBERON:000101371.97gold quality
heartUBERON:000094871.79gold quality
small intestineUBERON:000210871.47gold quality
heart left ventricleUBERON:000208471.27gold quality
lungUBERON:000204871.15gold quality
smooth muscle tissueUBERON:000113571.06gold quality
adenohypophysisUBERON:000219671.06gold quality
upper lobe of left lungUBERON:000895270.99gold quality
tonsilUBERON:000237270.87gold quality
small intestine Peyer’s patchUBERON:000345470.52gold quality
olfactory segment of nasal mucosaUBERON:000538670.48gold quality
apex of heartUBERON:000209870.26gold quality
body of stomachUBERON:000116170.25gold quality
popliteal arteryUBERON:000225070.15gold quality
thoracic mammary glandUBERON:000520070.14gold quality
tibial arteryUBERON:000761070.14gold quality
right uterine tubeUBERON:000130269.94gold quality

Single-cell (SCXA)

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

ExperimentMarker?Max mean expression
E-ANND-3yes3.37
E-MTAB-10290no294.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting ACKR4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-3646100.0073.565283
HSA-MIR-513A-5P100.0069.772465
HSA-MIR-6867-5P100.0082.213464
HSA-MIR-340-5P100.0072.504437
HSA-MIR-4795-3P100.0074.624024
HSA-MIR-371B-5P99.9975.344759
HSA-MIR-477599.9875.006394
HSA-MIR-548P99.9872.253784
HSA-MIR-520D-5P99.9873.344883
HSA-MIR-524-5P99.9873.434882
HSA-MIR-56899.9869.862084
HSA-MIR-373-5P99.9875.364753
HSA-MIR-616-5P99.9875.584775
HSA-MIR-590-3P99.9674.346478
HSA-MIR-493-5P99.9672.472382
HSA-MIR-1-3P99.9372.351914
HSA-MIR-20699.9372.501893
HSA-MIR-311999.9271.342390
HSA-MIR-129799.9173.413162
HSA-MIR-10527-5P99.9172.283754
HSA-MIR-61399.9171.501710
HSA-MIR-374A-5P99.9071.342923
HSA-MIR-374B-5P99.9069.982734
HSA-MIR-137-3P99.8774.742401
HSA-MIR-5582-3P99.8672.484221
HSA-MIR-629-3P99.8567.991875
HSA-MIR-76599.8468.242442
HSA-MIR-94499.8270.853042
HSA-MIR-430799.8270.453374
HSA-MIR-489-3P99.8066.46839

Literature-anchored findings (GeneRIF, showing 18)

  • Characterization of mouse CCX-CKR, a receptor for the lymphocyte-attracting chemokines TECK/mCCL25, SLC/mCCL21 and MIP-3beta/mCCL19: comparison to human CCX-CKR. (PMID:11981810)
  • Scavenges extracellular chemokines in vivo to modify responses through CCR7. (PMID:16791897)
  • Down regulation of CCX-CKR is associated with breast cancer. (PMID:19383822)
  • Data suggest that co-expression of CCX-CKR and CXCR3 (chemokine receptor type 3) in T-lymphocytes results in protein multimerization and prevents CXCR3-mediated chemotaxis; this represents a novel mechanism of regulation of immune cell migration. (PMID:23121557)
  • Results suggest that chemokine binding to CCX-CKR recruits Gi proteins and beta-arrestin (beta-arr) with high affinity. (PMID:23341447)
  • co-expression of DARC, D6, and CCX-CKR significantly associated with higher survival in gastric cancer (PMID:23462454)
  • Effect of genetic variants in two chemokine decoy receptor genes, DARC and CCBP2, on metastatic potential of breast cancer. (PMID:24260134)
  • we found that CCX-CKR expression in vitro could modulate cellular migration and invasion abilities, potentially via the regulation of other chemotactic factors/receptors. (PMID:24338720)
  • Results of this study show that HEK 293 cells express an endogenous CCRL1 gene only at mRNA level. These data therefore represent the important implications for the use of HEK 293 cells as a host cell system for the study of CCX-CKR. (PMID:26699909)
  • CCL19-mRFP and CCL21-mRFP are versatile and powerful tools to study CCR7 and ACKR4 functions. (PMID:30518137)
  • ACKR4 Recruits GRK3 Prior to beta-Arrestins but Can Scavenge Chemokines in the Absence of beta-Arrestins. (PMID:32391018)
  • Systematic reassessment of chemokine-receptor pairings confirms CCL20 but not CXCL13 and extends the spectrum of ACKR4 agonists to CCL22. (PMID:32480426)
  • CCL20 is a novel ligand for the scavenging atypical chemokine receptor 4. (PMID:32533638)
  • Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings. (PMID:33374792)
  • The relation between ACKR4 and CCR7 genes expression and breast cancer metastasis. (PMID:34102193)
  • Mechanosensitive ACKR4 scavenges CCR7 chemokines to facilitate T cell de-adhesion and passive transport by flow in inflamed afferent lymphatics. (PMID:35108538)
  • Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension. (PMID:37449198)
  • Atypical chemokine receptor 4 (ACKR4/CCX-CKR): A comprehensive exploration across physiological and pathological landscapes in contemporary research. (PMID:38597217)

Cross-species orthologs

4 orthologs

OrganismSymbolGene ID
danio_rerioackr4bENSDARG00000040133
danio_rerioackr4aENSDARG00000078729
mus_musculusAckr4ENSMUSG00000079355
rattus_norvegicusAckr4ENSRNOG00000011478

Paralogs (23): CCR6 (ENSG00000112486), CCRL2 (ENSG00000121797), CCR2 (ENSG00000121807), CXCR4 (ENSG00000121966), CCR7 (ENSG00000126353), ACKR3 (ENSG00000144476), ACKR2 (ENSG00000144648), RGR (ENSG00000148604), CXCR5 (ENSG00000160683), CCR5 (ENSG00000160791), CXCR1 (ENSG00000163464), CCR1 (ENSG00000163823), CX3CR1 (ENSG00000168329), CXCR6 (ENSG00000172215), XCR1 (ENSG00000173578), CCR9 (ENSG00000173585), CCR8 (ENSG00000179934), CXCR2 (ENSG00000180871), GALR2 (ENSG00000182687), CCR3 (ENSG00000183625), CCR4 (ENSG00000183813), CCR10 (ENSG00000184451), CXCR3 (ENSG00000186810)

Protein

Protein identifiers

Atypical chemokine receptor 4Q9NPB9 (reviewed: Q9NPB9)

Alternative names: C-C chemokine receptor type 11, CC chemokine receptor-like 1, CCX CKR

All UniProt accessions (2): Q9NPB9, H0Y9Z2

UniProt curated annotations — full annotation on UniProt →

Function. Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines CCL2, CCL8, CCL13, CCL19, CCL21 and CCL25. Chemokine-binding does not activate G-protein-mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization. Plays an important role in controlling the migration of immune and cancer cells that express chemokine receptors CCR7 and CCR9, by reducing the availability of CCL19, CCL21, and CCL25 through internalization. Negatively regulates CXCR3-induced chemotaxis. Regulates T-cell development in the thymus.

Subunit / interactions. Forms heteromers with CXCR3. Interacts with ARRB1 and ARRB2.

Subcellular location. Early endosome. Recycling endosome. Cell membrane.

Tissue specificity. Predominantly expressed in heart. Lower expression in lung, pancreas, spleen, colon, skeletal muscle and small intestine.

Post-translational modifications. The Ser/Thr residues in the C-terminal cytoplasmic tail may be phosphorylated.

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

RefSeq proteins (2): NP_057641, NP_848540 (=MANE)

Domains & families (InterPro)

IDNameType
IPR000276GPCR_RhodpsnFamily
IPR000355Chemokine_rcptFamily
IPR005383ACKR4Family
IPR017452GPCR_Rhodpsn_7TMDomain
IPR050119CCR1-9-likeFamily

Pfam: PF00001

UniProt features (19 total): topological domain 8, transmembrane region 7, glycosylation site 2, chain 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9NPB9-F181.550.36

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): 112–184

Glycosylation sites (2): 6, 19

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

IDPathway
R-HSA-380108Chemokine receptors bind chemokines
R-HSA-162582Signal Transduction
R-HSA-372790Signaling by GPCR
R-HSA-373076Class A/1 (Rhodopsin-like receptors)
R-HSA-375276Peptide ligand-binding receptors
R-HSA-500792GPCR ligand binding

MSigDB gene sets: 115 (showing top): GOBP_CELL_CHEMOTAXIS, GOBP_RESPONSE_TO_PEPTIDE, JAEGER_METASTASIS_DN, GOCC_CELL_SURFACE, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_TAXIS, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GARY_CD5_TARGETS_DN, WANG_CISPLATIN_RESPONSE_AND_XPC_DN, HU_GENOTOXIN_ACTION_DIRECT_VS_INDIRECT_4HR, VECCHI_GASTRIC_CANCER_EARLY_DN, chr3q22, TGGAAA_NFAT_Q4_01, GOCC_SIDE_OF_MEMBRANE, GOCC_RECYCLING_ENDOSOME

GO Biological Process (9): chemotaxis (GO:0006935), immune response (GO:0006955), G protein-coupled receptor signaling pathway (GO:0007186), positive regulation of cytosolic calcium ion concentration (GO:0007204), calcium-mediated signaling (GO:0019722), cell chemotaxis (GO:0060326), signal transduction (GO:0007165), vesicle-mediated transport (GO:0016192), chemokine-mediated signaling pathway (GO:0070098)

GO Molecular Function (7): chemokine receptor activity (GO:0004950), scavenger receptor activity (GO:0005044), C-C chemokine receptor activity (GO:0016493), C-C chemokine binding (GO:0019957), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515), chemokine binding (GO:0019956)

GO Cellular Component (6): early endosome (GO:0005769), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), recycling endosome (GO:0055037), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

CategoryPathways
Peptide ligand-binding receptors1
Signal Transduction1
GPCR ligand binding1
Class A/1 (Rhodopsin-like receptors)1
Signaling by GPCR1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular process2
G protein-coupled receptor signaling pathway2
chemokine binding2
endosome2
response to chemical1
taxis1
immune system process1
response to stimulus1
G protein-coupled receptor activity1
signal transduction1
regulation of biological quality1
intracellular signaling cassette1
chemotaxis1
cell migration1
cellular response to chemical stimulus1
cell communication1
signaling1
regulation of cellular process1
cellular response to stimulus1
transport1
cytokine-mediated signaling pathway1
cellular response to chemokine1
G protein-coupled chemoattractant receptor activity1
cytokine receptor activity1
chemokine-mediated signaling pathway1
cargo receptor activity1
chemokine receptor activity1
C-C chemokine binding1
transmembrane signaling receptor activity1
binding1
cytokine binding1
membrane1
cell periphery1
plasma membrane1
cell surface1
side of membrane1
endomembrane system1
cytoplasmic vesicle1
cellular anatomical structure1

Protein interactions and networks

STRING

1006 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
ACKR4CCL27Q9Y4X3998
ACKR4CCL21O00585997
ACKR4CCL25O15444995
ACKR4CCL19Q99731992
ACKR4CXCL13O43927990
ACKR4CCL17Q92583978
ACKR4CCL22O00626940
ACKR4CCL5P13501938
ACKR4CCL20P78556928
ACKR4CXCL12P48061858
ACKR4CCL8P78388816
ACKR4MADCAM1Q13477777
ACKR4ACKR1Q16570742
ACKR4CCL2P13500739
ACKR4NECTIN3Q9NQS3684

IntAct

5 interactions, top by confidence:

ABTypeScore
ACKR4SURF6psi-mi:“MI:0915”(physical association)0.400
ACKR4ATP12Apsi-mi:“MI:0915”(physical association)0.400
ACKR4CDK2psi-mi:“MI:0915”(physical association)0.370
ACKR4CXCR3psi-mi:“MI:2364”(proximity)0.270

BioGRID (8): CXCL13 (Reconstituted Complex), CCL21 (Reconstituted Complex), CCL25 (Reconstituted Complex), CCL19 (Reconstituted Complex), SURF6 (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ACKR4 (Positive Genetic), CDK2 (Two-hybrid)

ESM2 similar proteins: A1A5S3, A5PLE7, B0UXR0, B5X337, F5HDK1, F5HF62, F8VQN3, O00421, O18982, O97663, P09703, P32249, P35351, P35374, P46002, P49685, P50052, P51676, P56412, P69332, P69333, Q01035, Q0II78, Q0VDU3, Q14330, Q1RMI1, Q28929, Q3T0E9, Q3U507, Q4R613, Q6IYF9, Q75ZH0, Q83207, Q89609, Q8BZR0, Q8IYL9, Q8K1Z6, Q95N03, Q96P67, Q98146

Diamond homologs: O00574, O08556, O08565, O18793, O18983, O19024, O54689, O54814, O55193, O62743, O62747, O97571, O97878, O97879, O97880, O97881, O97883, O97962, O97975, P21109, P25025, P25930, P32246, P32248, P35343, P35344, P35350, P35407, P41597, P47774, P49682, P51677, P51678, P51679, P51680, P51681, P51683, P51684, P51686, P56439

SIGNOR signaling

3 interactions.

AEffectBMechanism
CCL19“up-regulates activity”ACKR4binding
CCL21“up-regulates activity”ACKR4binding
CCL25“up-regulates activity”ACKR4binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance1
Likely benign0
Benign0

Top pathogenic / likely-pathogenic (0)

SpliceAI

721 predictions. Top by Δscore:

VariantEffectΔscore
3:132597916:T:Gdonor_gain1.0000
3:132603221:ACACT:Adonor_loss1.0000
3:132603222:CACTC:Cdonor_loss1.0000
3:132603223:ACTCA:Adonor_loss1.0000
3:132603224:CTCA:Cdonor_loss1.0000
3:132603225:TCACC:Tdonor_loss1.0000
3:132603226:CA:Cdonor_loss1.0000
3:132603227:A:ACdonor_gain1.0000
3:132603228:C:CCdonor_gain1.0000
3:132603228:C:CTdonor_loss1.0000
3:132603228:CCA:Cdonor_gain1.0000
3:132603324:GGTT:Gacceptor_gain1.0000
3:132603325:GTT:Gacceptor_gain1.0000
3:132603326:TT:Tacceptor_gain1.0000
3:132603326:TTC:Tacceptor_loss1.0000
3:132603327:TCTA:Tacceptor_loss1.0000
3:132603328:C:CCacceptor_gain1.0000
3:132603328:CT:Cacceptor_loss1.0000
3:132603329:T:Aacceptor_loss1.0000
3:132618677:T:TAdonor_gain1.0000
3:132597916:T:TGdonor_gain0.9900
3:132597920:G:GGdonor_gain0.9900
3:132600384:TCTA:Tacceptor_loss0.9900
3:132600385:CTAGA:Cacceptor_loss0.9900
3:132600386:TAGA:Tacceptor_loss0.9900
3:132600387:A:AGacceptor_gain0.9900
3:132600387:A:Cacceptor_loss0.9900
3:132600388:G:GCacceptor_loss0.9900
3:132600388:G:GGacceptor_gain0.9900
3:132600388:GATT:Gacceptor_gain0.9900

AlphaMissense

2317 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
3:132600797:A:CS134R0.996
3:132600799:C:AS134R0.996
3:132600799:C:GS134R0.996
3:132600712:G:CW105C0.995
3:132600712:G:TW105C0.995
3:132600488:T:AC31S0.994
3:132600489:G:CC31S0.994
3:132600657:A:CD87A0.994
3:132600710:T:AW105R0.993
3:132600710:T:CW105R0.993
3:132600731:T:AC112S0.992
3:132600732:G:CC112S0.992
3:132600488:T:CC31R0.990
3:132600560:G:AG55R0.990
3:132600560:G:CG55R0.990
3:132600657:A:TD87V0.990
3:132600902:A:CS169R0.990
3:132600904:C:AS169R0.990
3:132600904:C:GS169R0.990
3:132600947:T:AC184S0.990
3:132600948:G:CC184S0.990
3:132601142:T:CF249L0.990
3:132601144:C:AF249L0.990
3:132601144:C:GF249L0.990
3:132600731:T:CC112R0.989
3:132600881:T:AW162R0.989
3:132600881:T:CW162R0.989
3:132601161:C:GP255R0.989
3:132600561:G:AG55E0.988
3:132600658:T:AD87E0.988

dbSNP variants (sampled 300 via entrez): RS1000006957 (3:132598059 A>G), RS1000054354 (3:132597749 C>T), RS1000847872 (3:132599532 A>T), RS1001008231 (3:132596366 C>A), RS1001060487 (3:132596072 C>A), RS1001298017 (3:132602559 TA>T,TAA), RS1001392425 (3:132602876 C>G,T), RS1001676846 (3:132599583 G>C), RS1001729371 (3:132599273 C>T), RS1002305250 (3:132600254 A>G), RS1003852378 (3:132602702 C>T), RS1004011931 (3:132602673 A>C), RS1004354036 (3:132601480 T>C), RS1005067464 (3:132598925 T>C), RS1005424945 (3:132599196 A>C)

Disease associations

OMIM: gene MIM:606065 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

StudyTraitp-value
GCST006622_17Neonatal cytokine/chemokine levels (fetal genetic effect)3.000000e-10
GCST010699_54Brain morphology (min-P)5.000000e-08
GCST010701_80Cortical surface area (MOSTest)5.000000e-09
GCST010702_60Subcortical volume (MOSTest)6.000000e-12
GCST010703_12Brain morphology (MOSTest)9.000000e-10

EFO canonical traits (4, from GWAS)

EFO IDTrait name
EFO:0004747protein measurement
EFO:0007959fetal genotype effect measurement
EFO:0009416CCL21 measurement
EFO:0004346neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Chemokine receptors

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

LigandActionAffinityParameter
CCL19Agonist8.4pKi
CCL25Agonist7.6pKi
CCL21Agonist6.9pKi

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

ChemicalActions (top 5)PubMed papers
Progesteronedecreases expression, increases expression2
perfluorooctanoic aciddecreases expression1
monomethylarsonous acidincreases expression1
incobotulinumtoxinAincreases expression1
Folic Acidaffects expression1
Nickelincreases expression1
Tetrachlorodibenzodioxinincreases expression1
Tobacco Smoke Pollutiondecreases expression1
Valproic Aciddecreases methylation1
Antirheumatic Agentsincreases expression1

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.