Biology:GPR15

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

G protein-coupled receptor 15 is a protein that in humans is encoded by the GPR15 gene.

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.[1][2] It is found in epithelial cells,[3] synovial macrophages,[4] endothelial cells [5] 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. [3] Protein expression in lymphocytes is strongly associated with hypomethylation of its gene. [6]

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. [3][7] In peripheral blood, GPR15 is mainly found on T cells, especially on CD4+ T helper cells, and less prominent on B cells. [8] 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. [9] With respect to the homing of GPR15-expressing immune cells to the colon there are divergent mechanisms between human and rodents like mouse. [10]

Ligands

There are at least two endogenous ligand found recently. One ligand encoded by the human gene GPR15LG was identified as a robust marker for psoriasis whose abundance decreased after therapeutic treatment with anti-interleukin-17 antibody. Transcripts of GPR15LG are abundant in cervix and colon. It is currently unknown whether GPR15LG 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. [11] The second ligand is a fragment of thrombomodulin exerting anti-inflammatory function in mice. [5]

Clinical significance

Human GPR15 was originally cloned as a co-receptor for HIV or the simian immunodeficiency virus. [7] HIV-induced activation of GPR15 in enterocytes seems to cause HIV enteropathy accompanied with diarrhea and lipid malabsorption. [3] 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. [9] In mouse, GPR15-deficient mice were prone to develop severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient T regs. [12]

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 [8] it does not indicate a disturbed homeostasis in the lung. [13]

References

  1. ↑ "A novel human gene encoding a G-protein-coupled receptor (GPR15) is located on chromosome 3". Genomics 32 (3): 462–465. March 1996. doi:10.1006/geno.1996.0143. PMID 8838812. 
  2. ↑ "Entrez Gene: GPR15 G protein-coupled receptor 15". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2838. 
  3. ↑ 3.0 3.1 3.2 3.3 "Gp120-induced Bob/GPR15 activation: a possible cause of human immunodeficiency virus enteropathy". The American Journal of Pathology 159 (5): 1933–1939. November 2001. doi:10.1016/S0002-9440(10)63040-4. PMID 11696454. 
  4. ↑ "Orphan receptor GPR15/BOB is up-regulated in rheumatoid arthritis". Cytokine 67 (2): 53–59. June 2014. doi:10.1016/j.cyto.2014.02.015. PMID 24725539. 
  5. ↑ 5.0 5.1 "G-protein coupled receptor 15 mediates angiogenesis and cytoprotective function of thrombomodulin". Scientific Reports 7 (1): 692. April 2017. doi:10.1038/s41598-017-00781-w. PMID 28386128. Bibcode: 2017NatSR...7..692P. 
  6. ↑ "A varying T cell subtype explains apparent tobacco smoking induced single CpG hypomethylation in whole blood". Clinical Epigenetics 7 (1): 81. 2015. doi:10.1186/s13148-015-0113-1. PMID 26246861. 
  7. ↑ 7.0 7.1 "Expression cloning of new receptors used by simian and human immunodeficiency viruses". Nature 388 (6639): 296–300. July 1997. doi:10.1038/40894. PMID 9230441. 
  8. ↑ 8.0 8.1 "Specific induction of the unique GPR15 expression in heterogeneous blood lymphocytes by tobacco smoking". Biomarkers 24 (3): 217–224. May 2019. doi:10.1080/1354750X.2018.1539769. PMID 30387691. https://figshare.com/articles/dataset/Specific_induction_of_the_unique_GPR15_expression_in_heterogeneous_blood_lymphocytes_by_tobacco_smoking/11171342. 
  9. ↑ 9.0 9.1 "Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo". Gut 65 (10): 1642–1664. October 2016. doi:10.1136/gutjnl-2015-310022. PMID 26209553. 
  10. ↑ "GPR15: a tale of two species". Nature Immunology 16 (2): 137–139. February 2015. doi:10.1038/ni.3084. PMID 25594457. 
  11. ↑ "A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia". Science Signaling 10 (496). September 2017. doi:10.1126/scisignal.aal0180. PMID 28900043. 
  12. ↑ "GPR15-mediated homing controls immune homeostasis in the large intestine mucosa". Science 340 (6139): 1456–1459. June 2013. doi:10.1126/science.1237013. PMID 23661644. Bibcode: 2013Sci...340.1456K. 
  13. ↑ "Tobacco-smoking induced GPR15-expressing T cells in blood do not indicate pulmonary damage". BMC Pulmonary Medicine 17 (1): 159. November 2017. doi:10.1186/s12890-017-0509-0. PMID 29183299. 

Further reading



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