Horse CXCR3 (C-X-C chemokine receptor type 3, also called the IP-10 receptor) is a rhodopsin-like seven-transmembrane G protein-coupled receptor of the plasma membrane. By orthology with the experimentally characterised human and mouse receptors, which sit in the same PANTHER subfamily (PTHR10489:SF671), it binds the interferon-inducible C-X-C chemokines CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC) and transduces their signal through heterotrimeric Gi proteins, mobilising intracellular calcium and directing the chemotaxis of activated effector (type-1) T lymphocytes and other leukocytes toward sites of interferon-driven inflammation. The 369-residue product conserves the human ligand-recognition N terminus (including the two sulfated tyrosines), the conserved extracellular disulfide and the DRY motif. In horses, CXCR3 transcripts are detected in blood leukocytes and wounded skin, but ligand binding and signalling of the horse receptor have not been tested directly. Human CXCR3 also has a splice variant (CXCR3-B) with an extended N terminus that binds CXCL4 and mediates angiostatic signalling; whether horses make an equivalent isoform is unknown.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002685 regulation of leukocyte migration | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping from the CXCR3-specific signature (IPR004070). CXCR3 signalling steers leukocyte (mainly activated T-cell) migration toward CXCL9/10/11; the receptor's own role is better captured by T cell chemotaxis and chemokine-mediated signalling, so this regulation term is true but peripheral. Reason: The horse protein is in PANTHER subfamily PTHR10489:SF671 with human P49682 (90.8% identity, full-length) and mouse/dog/bovine CXCR3, so the human ligand-driven leukocyte migration evidence transfers. In human, CXCR3 engagement by CXCL9/10/11 drives chemotaxis of Th1 cells, NK cells, macrophages and dendritic cells. The receptor directly mediates chemotaxis (captured on the chemotaxis row, refined to T cell chemotaxis) rather than acting as a modulator of a migration process driven by something else, so this regulation term is retained only as non-core. Supporting Evidence: PMID:12782716 the interaction of CXCL9, CXCL10, and CXCL11 with CXCR3 also results in the chemotaxis of activated Th1 cells (17, 18), NK cells (19), macrophages (20), and dendritic cells (21) file:HORSE/CXCR3/CXCR3-bioinformatics/RESULTS-rereview.md | P49682 | CXCR3_HUMAN | 368 | PTHR10489:SF671 | 0.908 | 368 | |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000120 | MODIFY | Summary: Correct (rhodopsin-like 7TM GPCR with conserved DRY motif and C125-C204 disulfide), but entailed by the more specific C-X-C chemokine receptor activity that the gene also carries. Reason: The receptor is a class A GPCR, but the evidence supports the specific activity C-X-C chemokine receptor activity (GO:0016494, an is_a descendant of GO:0004930 via chemokine receptor activity), which the gene already carries from the CXCR3 signature. Human CXCR3 mediates Ca2+ mobilisation in response to IP10 and Mig; the horse ortholog conserves the DRY motif and the extracellular disulfide. Proposed replacements: C-X-C chemokine receptor activity Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in file:HORSE/CXCR3/CXCR3-bioinformatics/RESULTS-rereview.md | 149 | R | 150 | R | |
| GO:0004950 chemokine receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general; CXCR3 is selective for the C-X-C chemokines CXCL9, CXCL10 and CXCL11, so the specific C-X-C chemokine receptor activity term applies. Reason: Human CXCR3 is selective for CXC chemokines IP10/CXCL10 and Mig/CXCL9 (plus CXCL11) and does not respond to the CC chemokines tested. The horse protein is a full-length SF671 ortholog, so the specific child term GO:0016494, already carried by this gene, is the appropriate refinement. Proposed replacements: C-X-C chemokine receptor activity Supporting Evidence: PMID:9064356 A human receptor that is selective for the CXC chemokines IP10 and Mig file:human/CXCR3/CXCR3-uniprot.txt Receptor for the C-X-C chemokines CXCL9, CXCL10 |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane is the site of CXCR3 ligand recognition and G-protein coupling; seven Phobius-predicted transmembrane helices in the horse sequence and experimental cell-membrane localisation of human CXCR3 support it. Reason: Human CXCR3 isoforms localise to the cell membrane experimentally (UniProt, citing PMID:12782716), and the horse ortholog has the seven transmembrane helices and extracellular N-terminal ligand-binding region of the receptor. Supporting Evidence: file:human/CXCR3/CXCR3-uniprot.txt Cell membrane {ECO:0000269|PubMed:12782716}; Multi-pass membrane protein file:HORSE/CXCR3/CXCR3-uniprot.txt TRANSMEM 307..326 |
| GO:0006935 chemotaxis | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general. CXCR3 is the chemotactic receptor of activated (effector) T lymphocytes, so T cell chemotaxis is the supported specific term. Reason: Human CXCR3 mediates chemotaxis in response to IP10 and Mig, is highly expressed on IL-2-activated T lymphocytes, and drives chemotaxis of activated Th1 cells; the horse receptor is its full-length ortholog in the same PANTHER subfamily. GO:0010818 T cell chemotaxis is an is_a descendant of chemotaxis. The receptor also directs other leukocytes (NK cells, macrophages, dendritic cells), but T cells are its best established target. Proposed replacements: T cell chemotaxis Supporting Evidence: PMID:9064356 The IP10/Mig receptor is highly expressed in IL-2-activated T PMID:12782716 the interaction of CXCL9, CXCL10, and CXCL11 with CXCR3 also results in the chemotaxis of activated Th1 cells (17, 18) |
| GO:0006954 inflammatory response | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: CXCR3 recruits effector T cells to interferon-driven inflammatory sites; a contextual, non-core process for the receptor. Reason: The receptor's direct role is chemokine signalling and T-cell chemotaxis; its contribution to inflammation is through recruitment of effector lymphocytes. Horse CXCR3 transcripts are found in wounded cutaneous tissue alongside its ligand CXCL10, consistent with an inflammatory context, but expression is not functional evidence. Kept as non-core rather than removed because recruitment of inflammatory effector cells is part of the inflammatory response. Supporting Evidence: PMID:9064356 involved in the selective recruitment of effector T cells PMID:31256888 CXCL10 and its receptor CXCR3 are involved in inflammation resolution |
| GO:0007165 signal transduction | IEA GO_REF:0000104 | MODIFY | Summary: True but very general; the receptor's signalling is specifically chemokine-mediated G protein-coupled signalling. Reason: The previous review left this UNDECIDED, but the claim itself is not in doubt: ligand-activated CXCR3 transduces chemokine signals (Ca2+ mobilisation, chemotaxis). The appropriate specific term is GO:0070098 chemokine-mediated signaling pathway, an is_a descendant of signal transduction already carried by this gene. Proposed replacements: chemokine-mediated signaling pathway Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | MODIFY | Summary: Correct but general; chemokine-mediated signaling pathway (an is_a descendant) is the specific pathway this receptor initiates. Reason: Human CXCR3 signals through a heterotrimeric G-protein pathway in response to CXCL9/10/11; GO:0070098 chemokine-mediated signaling pathway is_a GO:0007186 and is already carried by this gene. Proposed replacements: chemokine-mediated signaling pathway Supporting Evidence: file:human/CXCR3/CXCR3-uniprot.txt Receptor for the C-X-C chemokines CXCL9, CXCL10 |
| GO:0009986 cell surface | IEA GO_REF:0000117 | ACCEPT | Summary: CXCR3 is exposed at the cell surface where it binds extracellular chemokines; consistent with its plasma-membrane location. Reason: The ARBA prediction is consistent with the receptor's topology and with human CXCR3 cell-membrane localisation; HMEC-1 cells transfected with either CXCR3 isoform bound the CXCR3 chemokines at the cell surface. Kept as a valid location alongside plasma membrane. Supporting Evidence: PMID:12782716 Human microvascular endothelial cell line-1 (HMEC-1), transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B. file:human/CXCR3/CXCR3-uniprot.txt Cell membrane {ECO:0000269|PubMed:12782716}; Multi-pass membrane protein |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Correct but uninformative; the receptor is located in the plasma membrane, a descendant term the gene already carries. Reason: Previously kept as non-core, but the guideline for a correct but general term is MODIFY to the supported specific descendant. Plasma membrane (GO:0005886, is_a membrane) is supported by human experimental localisation and by the horse seven-helix topology. Proposed replacements: plasma membrane Supporting Evidence: file:human/CXCR3/CXCR3-uniprot.txt Cell membrane {ECO:0000269|PubMed:12782716}; Multi-pass membrane protein |
| GO:0016494 C-X-C chemokine receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Core molecular function: receptor for the C-X-C chemokines CXCL9, CXCL10 and CXCL11, transferred by orthology within PANTHER subfamily PTHR10489:SF671. Reason: Human CXCR3 (same PANTHER subfamily, 90.8% identity over its full length) binds and responds to CXCL9, CXCL10 and CXCL11 but not to the other CXC or CC chemokines tested. The horse protein conserves the N-terminal sulfotyrosine sites (Y27, Y29) that contribute to chemokine recognition in human, the extracellular disulfide and the DRY motif, and clusters with the mammalian CXCR3 orthologs rather than with CXCR1, CXCR2, CXCR4 or CCR5. Horse-specific ligand pharmacology has not been tested. Supporting Evidence: PMID:12782716 Human microvascular endothelial cell line-1 (HMEC-1), transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B. PMID:9064356 A human receptor that is selective for the CXC chemokines IP10 and Mig file:HORSE/CXCR3/CXCR3-bioinformatics/RESULTS-rereview.md | 27 | Y | 27 | Y | |
| GO:0070098 chemokine-mediated signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Core process: CXCR3 initiates chemokine-mediated G protein-coupled signalling (Ca2+ mobilisation, chemotaxis) in response to CXCL9/10/11. Reason: Directly follows from the receptor activity; human CXCR3 mediates Ca2+ mobilisation and chemotaxis in response to IP10 and Mig, and the horse ortholog is a full-length SF671 member with conserved signalling motifs. Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in file:HORSE/CXCR3/CXCR3-bioinformatics/RESULTS-rereview.md | P49682 | CXCR3_HUMAN | 368 | PTHR10489:SF671 | 0.908 | 368 | |
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Download this section (compressed HTML)Q: Does the horse CXCR3 locus encode a CXCR3-B-like isoform with an alternative N-terminal exon (as in human), and does the 23-residue N-terminal extension of the second horse model F6U4S6 correspond to a real transcript or a gene-model artefact?
Q: Does horse CCL21 act on horse CXCR3 (as reported for mouse) or not (as for human)?
Experiment: Express horse CXCR3 (A0A9L0T1D1) in a reporter cell line and measure binding, Ca2+ flux and chemotaxis in response to equine CXCL9, CXCL10, CXCL11, CXCL4 and CCL21, with pertussis toxin to test Gi dependence.
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Download this section (compressed HTML)The downloaded human P49682 sequence (368 residues) and selected horse A0A9L0T1D1 sequence (369 residues) share 90.8% identity among 368 paired residues. Paired coverage is 100.0% of human and 99.7% of horse.
Full alignment, hashes, parameters and reproducible script: CXCR3.json and compare.py.
Pairwise similarity supports homology but does not establish reciprocal orthology, intact gene models, conservation of targeting signals or every biological claim. Current UniProt sequences are compared; identity with the original ProtNLM input sequence is unverified.
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