GPR15

GPR15 is a class A orphan G protein-coupled receptor (heterotrimeric guanine nucleotide-binding protein, GPCR). The GPR15 gene is localized at chromosome 3q11.2-q13.1.[4][5] It is found in epithelial cells [6], synovial macrophages [7], endothelial cells [8] and lymphocytes especially T cells. From the mRNA sequence a 40.8 kD molecular weight of GPR15 is proposed. In an epithelial tumour cell line (HT-29), however, a 36 kD band, composed of GPR15 and galactosyl ceramide, was detected. [6] Protein expression in lymphocytes is strongly associated with hypomethylation of its gene. [9]

GPR15
Identifiers
AliasesGPR15, BOB, G protein-coupled receptor 15
External IDsOMIM: 601166 MGI: 1918473 HomoloGene: 3869 GeneCards: GPR15
Gene location (Human)
Chr.Chromosome 3 (human)[1]
Band3q11.2Start98,531,978 bp[1]
End98,534,681 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

2838

71223

Ensembl

ENSG00000154165

ENSMUSG00000047293

UniProt

P49685

Q0VDU3

RefSeq (mRNA)

NM_005290

NM_001162955

RefSeq (protein)

NP_005281

NP_001156427

Location (UCSC)Chr 3: 98.53 – 98.53 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Tissue distribution
High gene expression was described for colonic mucosa, small bowel mucosa, liver and spleen. Moderate gene expression was found in blood, lymph node, thymus, testis and prostate. [6][10] In peripheral blood, GPR15 is mainly found on T cells, especially on CD4+ T helper cells, and less prominent on B cells. [11] By immunohistochemistry GPR15 is found specifically in glandular cells of the stomach, α-cells of islet of Langerhans in pancreas, surface epithelium of small intestine and colon, hepatocytes in liver, tubular epithelium of the kidney and in diverse tumour tissues such as glioblastoma, melanoma, small cell lung carcinoma or colon carcinoma.


Function
The overall physiological role remains elusive. It seems to play a role in homing of single T cell types to the colon. In human, GPR15 controls together with α4β7-integrin the homing of effector T cells to the inflamed gut of ulcerative colitis. [12] With respect to the homing of GPR15-expressing immune cells to the colon there are divergent mechanisms between human and rodents like mouse. [13]

Ligands
There are at least two endogenous ligand found recently. One ligand encoded by the human gene C10orf99 was identified as a robust marker for psoriasis whose abundance decreased after therapeutic treatment with anti-interleukin-17 antibody. Transcripts of C10orf99 are abundant in cervix and colon. It is currently unknown whether C10orf99 causes disease symptoms or is the consequence of a disturbed epithelial barrier. It does not act as a chemotactic agent but rather decrease T cell migration suggesting a mechanism of heterologous receptor desensitization. [14] The second ligand is a fragment of thrombomodulin exerting anti-inflammatory function in mice. [8]

Clinical significance
Human GPR15 was originally cloned as a co-receptor for HIV or the simian immunodeficiency virus. [10] HIV-induced activation of GPR15 in enterocytes seems to cause HIV enteropathy accompanied with diarrhea and lipid malabsorption. [6] In inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis the proportion of GPR15-expressing cells among regulatory T cells is slightly increased in peripheral blood. [12] In mouse, GPR15-deficient mice were prone to develop severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient T regs. [15]

Lifestyle
Chronic tobacco smoking is a very strong inducer of GPR15-expressing T cells in peripheral blood. Although the proportion of GPR15-expressing cells among T-cells in peripheral blood is a high sensitive and specific biomarker for chronic tobacco smoking [11] it does not indicate a disturbed homeostasis in the lung. [16]

References
  1. GRCh38: Ensembl release 89: ENSG00000154165 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. Heiber M, Marchese A, Nguyen T, Heng HH, George SR, O'Dowd BF (Feb 1997). "A novel human gene encoding a G-protein-coupled receptor (GPR15) is located on chromosome 3". Genomics. 32 (3): 462–465. doi:10.1006/geno.1996.0143. PMID 8838812.
  5. "Entrez Gene: GPR15 G protein-coupled receptor 15".
  6. Clayton F, Kotler DP, Kuwada SK, Morgan T, Stepan C, Kuang J, Le J and Fantini J. (2001). Gp120-induced Bob/GPR15 activation: a possible cause of human immunodeficiency virus enteropathy. Am J Pathol 159:1933-9.PMC1867054/pdf/2900.pdf
  7. Cartwright A, Schmutz C, Askari A, Kuiper JH and Middleton J. (2014). Orphan receptor GPR15/BOB is up-regulated in rheumatoid arthritis. Cytokine 67:53–9.24725539[uid]
  8. Pan B, Wang X, Nishioka C, Honda G, Yokoyama A, Zeng L, Xu K and Ikezoe T. (2017). G-protein coupled receptor 15 mediates angiogenesis and cytoprotective function of thrombomodulin. Sci Rep 7:692.781.pdf
  9. Bauer M, Linsel G, Fink B, Offenberg K, Hahn AM, Sack U, Knaack H, Eszlinger M and Herberth G. (2015). A varying T cell subtype explains apparent tobacco smoking induced single CpG hypomethylation in whole blood. Clin Epigenetics 7:81.PMC4526203
  10. Deng HK, Unutmaz D, KewalRamani VN and Littman DR. (1997). Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature 388:296–300.40894.pdf
  11. Bauer M, Hackermuller J, Schor J, Schreiber S, Fink B, Pierzchalski A and Herberth G. (2018). Specific induction of the unique GPR15 expression in heterogeneous blood lymphocytes by tobacco smoking. Biomarkers:1–8.30387691
  12. Fischer A, Zundler S, Atreya R, Rath T, Voskens C, Hirschmann S, Lopez-Posadas R, Watson A, Becker C, Schuler G, Neufert C, Atreya I and Neurath MF. (2015). Differential effects of alpha4beta7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut.PMC5036234
  13. Bilsborough J and Viney JL. (2015). GPR15: a tale of two species. Nat Immunol 16:137-9.3084.pdf
  14. Suply T, Hannedouche S, Carte N, Li J, Grosshans B, Schaefer M, Raad L, Beck V, Vidal S, Hiou-Feige A, Beluch N, Barbieri S, Wirsching J, Lageyre N, Hillger F, Debon C, Dawson J, Smith P, Lannoy V, Detheux M, Bitsch F, Falchetto R, Bouwmeester T, Porter J, Baumgarten B, Mansfield K, Carballido JM, Seuwen K and Bassilana F. (2017). A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia. Sci Signal 10.28900043
  15. Kim SV, Xiang WV, Kwak C, Yang Y, Lin XW, Ota M, Sarpel U, Rifkin DB, Xu R and Littman DR. (2013). GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science 340:1456-9.1456.full.pdf
  16. Bauer M, Fink B, Seyfarth HJ, Wirtz H and Frille A. (2017). Tobacco-smoking induced GPR15-expressing T cells in blood do not indicate pulmonary damage. BMC Pulm Med 17:159.PMC5706341/pdf

Further reading
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