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.[5] The gene and protein structure of human PSGL-1 was first discovered in 1993. The research team at Genetics Institute (GI) named the molecule PSGL-1 for "P-selectin glycoprotein ligand-1" although it was found to also bind the other two selectins types.[6] In 1994, the GI team now led by Gray Shaw discovered that most of the binding activity of PSGL-1 was localized within its N-terminal 19 amino acids, including three sulfotyrosines (Tys) at positions 5, 7 and 10 and a critical O-linked glycan attached to the threonine at position 16 of the mature, fully processed PSGL-1 present on a cell's surface. They termed this the "anionic segment" of PSGL-1 in 1995[7] and then published the co-crystal structure of human PSGL-1's anionic segment bound to human P-selectin in 2000.[8]
The organization of the SELPLG gene closely resembles that ofCD43 and the human platelet glycoproteinGpIb-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.[9][10]
P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric mucin-likeglycoprotein found primarily on the surface ofwhite blood cells. PSGL-1 can serve as a ligand forP-selectin (P stands forplatelet), which is one of a family of selectins that includesE-selectin (endothelial) andL-selectin (leukocyte). Selectins are part of the broader family ofcell 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.
PSGL-1 is expressed on allwhite 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 theendothelium 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.[15] In 2000 it was reported that PSGL-1 can also be expressed on the surface of platelets, although at a substantially lower level than that seen on the surface of leukocytes.[16]
The systemic administration of soluble recombinant forms of human PSGL-1 such as rPSGL-Ig or TSGL-Ig can preventreperfusion 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.[17][18]
In mice PSGL-1 acts as an immune factor regulating multipleT-cell checkpoints. Consequently, the antagonsim of PSGL-1 engagement and signaling has been proposed as a promising target for futurecheckpoint inhibitor anti-cancer drugs.[19]
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).[20]
In mice, PSGL-1 seems to facilitateT cell exhaustion in tumors.[21] 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.[22] 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.[23] It has been noted that the abundant expression of PSGL-1, on the surface of so many different hematopoeitic cell types, causes a target-mediated drug disposition (TMDD) problem or crosslinking problems for antibodies that bind and target PSGL-1.[21][24] The use of recombinant forms of PSGL-1 avoids the TMDD problem.
PSGL-1 is also a phagocytosis ("don't eat me") checkpoint molecule that is distinct from the CD47-SIRPα pathway. Deficiency or antagonism of PSGL-1 on cells (such as hematologic cancer cells) promotes their phagocytosis by macrophages.[25]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Veerman KM, Carlow DA, Shanina I, Priatel JJ, Horwitz MS, Ziltener HJ (February 2012). "PSGL-1 regulates the migration and proliferation of CD8(+) T cells under homeostatic conditions".Journal of Immunology.188 (4):1638–1646.doi:10.4049/jimmunol.1103026.PMID22250093.
^Sako D, Chang XJ, Barone KM, Vachino G, White HM, Shaw G, et al. (December 1993). "Expression cloning of a functional glycoprotein ligand for P-selectin".Cell.75 (6):1179–1186.doi:10.1016/0092-8674(93)90327-m.PMID7505206.
^Somers WS, Tang J, Shaw GD, Camphausen RT (October 2000). "Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLe(X) and PSGL-1".Cell.103 (3):467–479.doi:10.1016/s0092-8674(00)00138-0.PMID11081633.
^Zarbock A, Müller H, Kuwano Y, Ley K (November 2009). "PSGL-1-dependent myeloid leukocyte activation".Journal of Leukocyte Biology.86 (5):1119–1124.doi:10.1189/jlb.0209117.PMID19703898.
^Zhong C, Wang L, Liu Y, Wang X, Xia Z, Li Y, et al. (June 2025). "PSGL-1 is a phagocytosis checkpoint that enables tumor escape from macrophage clearance".Science Immunology.10 (108) eadn4302.doi:10.1126/sciimmunol.adn4302.PMID40512837.
Furie B, Furie BC (April 2004). "Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation".Trends in Molecular Medicine.10 (4):171–178.doi:10.1016/j.molmed.2004.02.008.PMID15059608.
Sako D, Chang XJ, Barone KM, Vachino G, White HM, Shaw G, et al. (December 1993). "Expression cloning of a functional glycoprotein ligand for P-selectin".Cell.75 (6):1179–1186.doi:10.1016/0092-8674(93)90327-M.PMID7505206.S2CID23786141.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides".Gene.138 (1–2):171–174.doi:10.1016/0378-1119(94)90802-8.PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library".Gene.200 (1–2):149–156.doi:10.1016/S0378-1119(97)00411-3.PMID9373149.
