PSGL-1

Selectin P ligand, also known as SELPLG or CD162 (cluster of differentiation 162), is a human gene.

SELPLG codes for PSGL-1, the high affinity counter-receptor for P-selectin on myeloid cells and stimulated T lymphocytes. As such, it plays a critical role in the tethering of these cells to activated platelets or endothelia expressing P-selectin. Naive and stimulated lymphocytes appear to use PSGL-1 for trafficking into and out of lymph nodes. The gene and structure of human PSGL-1 was first reported in 1993. In 1995, most of the binding activity of PSGL-1 was localized within its N-terminal 19 amino acids, including the sulfotyrosines (Tys) at positions 5, 7 and 10 and the critical O-linked glycan attached to the threonine at position 16 of the mature, fully processed PSGL-1 present on a cell's surface. The co-crystal structure of human PSGL-1 bound to human P-selectin was published in 2000.

https://www.cell.com/cms/10.1016/S0092-8674(00)00138-0/asset/b4d95b05-fc96-4a34-837a-48bcb954f05e/main.assets/gr5_lrg.jpg

The organization of the SELPLG gene closely resembles that of CD43 and the human platelet glycoprotein GpIb-alpha both of which have an intron in the 5-prime-noncoding region, a long second exon containing the complete coding region, and TATA-less promoters.

P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric mucin-like glycoprotein found primarily on the surface of white blood cells cells. PSGL-1 can serve as a ligand for P-selectin (P stands for platelet), which is one of a family of selectins that includes E-selectin (endothelial) and L-selectin (leukocyte). Selectins are part of the broader family of cell adhesion molecules. PSGL-1 can bind to each of the three members of the family but binds best (with the highest affinity) to P-selectin.

Posttranslational modification

PSGL-1 protein requires two distinct posttranslational modifications to gain its selectin binding activity:
* sulfation of tyrosines
* the addition of the sialyl Lewis x tetrasaccharide (sLex) to its O-linked glycans

Function

PSGL-1 is expressed on all white blood cells and plays an important role in the recruitment of white blood cells into inflamed tissue: White blood cells normally do not interact with the endothelium of blood vessels. However, inflammation causes the expression of cell adhesion molecules (CAM) such as P-selectin on the surface of the blood vessel wall. White blood cells present in flowing blood can interact with CAM. The first step in this interaction process is carried out by PSGL-1 interacting with P-selectin and/or E-selectin on endothelial cells and adherent platelets. This interaction results in "rolling" of the white blood cell on the endothelial cell surface followed by stable adhesion and transmigration of the white blood cell into the inflamed tissue.

Clinical significance

In inflammation

The systemic administration of soluble recombinant forms of human PSGL-1 such as rPSGL-Ig or TSGL-Ig can prevent reperfusion injury caused by leukocyte influx after an ischemic insult to various types of vascularized tissues (IRI). The protective effects of soluble recombinant forms of PSGL-1, acting as pan-selectin antagonists, has been studied in multiple animal models of solid organ transplant and ARDS.

In cancer

In mice PSGL-1 acts as an immune factor regulating multiple T-cell checkpoints. Consequently, the antagonsim of PSGL-1 engagement and signaling has been proposed as a promising target for future checkpoint inhibitor anti-cancer drugs.;

PSGL-1 has been shown to bind to VISTA (V-domain Ig suppressor of T cell activation) but this binding only occurs under acidic pH conditions (pH < 6.5) such as can be found in tumor microenvironments (TME).

In mice, PSGL-1 seems to facilitate T cell exhaustion in tumors.; PSGL-1 deficient mice treated with anti-PD-1 antibodies show a dramatic reduction in the growth of melanoma tumors as compared with wild-type mice treated with anti-PD-1 antibodies. Treatments with either soluble recombinant forms of PSGL-1 (PSGL-Ig) or monoclonal antibodies that bind and block PSGL-1 also reduce tumor growth in mouse models, especially when combined with anti-PD-1 monoclonal antibody treatments.

References

Further reading

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External links

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{{Clusters of differentiation

Clusters of differentiation
Receptors