P2RY8

Official Full Name

P2Y receptor family member 8

Organism

Homo sapiens

GeneID

286530

Background

The protein encoded by this gene belongs to the family of G-protein coupled receptors, that are preferentially activated by adenosine and uridine nucleotides. This gene is moderately expressed in undifferentiated HL60 cells, and is located on both chromosomes X and Y. [provided by RefSeq, Jul 2008]

Synonyms

P2Y8;

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Detailed Information

S-Geranylgeranyl-L-glutathione working as a ligand for P2RY8 receptor

Germinal centers play a pivotal role in antibody diversification, affinity diversification, and the malignancies of B cell. The confinement of germinal centers within B cell follicles is incompletely understood till now. P2ry8 can mediate the inhibition of migration and regulation of B cells growth in lymphoid tissues by acting as a Gα13-coupled receptor. Due to its frequent mutations in germinal-center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) and Burkitt lymphoma, the identification of the ligand for this receptor seems to be crucial. In research of the ligand identification for P2RY8 receptor, a seven-step biochemical fraction procedure and a drop-out mass spectrometry approach were used. A previously undescribed biomolecule, S-geranylgeranyl-L-glutathione (GGG) was found to be a potent P2RY8 ligand with a detectable nanomolar level in the lymphoid tissues, and it can inhibit the chemokine-mediated migration of human germinal-center B cells and T follicular helper cells. Gamma-glutamyltransferase-5 (GGT5), an enzyme with highly-expression in the follicular dendritic cells, can metabolize GGG into a form that did not activate the receptor. Promotion effect of P2RY8 for the B cell confinement to germinal centers can be disrupted by overexpression of GGT5, and GGG gradient can be formed by GGT5 in lymphoid tissues. For the role of the P2RY8 receptor in the progression of several types of cancer in addition to GCB-DLBCL and Burkitt lymphoma, GGG was speculated to be capable of organizing and growth-regulating in multiple human tissues.

P2RY8 receptor associated with follicular dendritic cells to promote germinal center confinement of B cells

Human germinal center (GC)-derived lymphomas related orphan Gα13-coupled receptor P2RY8 mutation was found to be able to promote B cell association with GCs in the mouse model. Germinal centers (GCs) are discrete, tightly organized clusters of GC B cells and T follicular helper cells (Tfh cells) in the center of reactive follicles. During the selection events necessary for antibody affinity maturation, confinement of GC B cells to GC is playing an important role in fostering the interactions between the antigen-loaded follicular DCs and Tfh cells. It was frequently found in human lymphomas derived from GC B cells that function mutations of S1PR2, P2RY8, GNA13 were lost. Spread of these malignancies to distant sites is associated with a poor prognosis. No orthologues have been identified in the mouse for the absence of X chromosome in rodents, where the P2RY8 gene is located on a portion of the pseudo autosomal region.

Figure 1. Role of P2RY8 receptor in immunological tolerance. (Yuke He, et al. 2021)

References:

Lu E, Wolfreys F D, Muppidi J R, et al. S-Geranylgeranyl-L-glutathione is a ligand for human B cell-confinement receptor P2RY8. Nature, 2019, 567(7747): 244-248.
Muppidi J R, Lu E, Cyster J G. The G protein–coupled receptor P2RY8 and follicular dendritic cells promote germinal center confinement of B cells, whereas S1PR3 can contribute to their dissemination. Journal of Experimental Medicine, 2015, 212(13): 2213-2222.
He Y, Gallman A E, Xie C, et al. P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance. Journal of Experimental Medicine, 2021, 219(1): e20211004.

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