P-selectin glycoprotein ligand-1

If there is something that has always fascinated us, it is P-selectin glycoprotein ligand-1. Since time immemorial, P-selectin glycoprotein ligand-1 has been an object of study, admiration and debate. Whether for its impact on history, its influence on culture, or its relevance in today's society, P-selectin glycoprotein ligand-1 continues to be a topic of great interest to academics, professionals, and the curious alike. In this article, we will thoroughly explore all aspects related to P-selectin glycoprotein ligand-1, from its origins to its impact on the modern world. Through a thorough and enriching analysis, we hope to expand our knowledge and understanding of P-selectin glycoprotein ligand-1, and perhaps even discover new facets that surprise us. Join us on this fascinating journey through P-selectin glycoprotein ligand-1, and together we will unravel its mysteries and meanings. Do not miss it!

SELPLG
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSELPLG, CD162, CLA, PSGL-1, PSGL1, selectin P ligand
External IDsOMIM: 600738; MGI: 106689; HomoloGene: 2261; GeneCards: SELPLG; OMA:SELPLG - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6404

20345

Ensembl

ENSG00000110876

ENSMUSG00000048163

UniProt

Q14242

Q62170

RefSeq (mRNA)

NM_001206609
NM_003006

NM_009151

RefSeq (protein)

NP_001193538
NP_002997

n/a

Location (UCSC)Chr 12: 108.62 – 108.63 MbChr 5: 113.96 – 113.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] The gene and structure of human PSGL-1 was first reported in 1993.[6] 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.[7] The co-crystal structure of human PSGL-1 bound to human P-selectin was published in 2000.[8]

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.[9][10]

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:[11][12][13][14]

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.[15]

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.[16][17]

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.[18]

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).[19]

In mice, PSGL-1 seems to facilitate T cell exhaustion in tumors.[20] 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.[21] 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.[22]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000110876 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000048163 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Veerman KM, Carlow DA, Shanina I, Priatel JJ, Horwitz MS, Ziltener HJ (2012-02-15). "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. ISSN 1550-6606. PMID 22250093.
  6. ^ 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. PMID 7505206.
  7. ^ Sako D, Comess KM, Barone KM, Camphausen RT, Cumming DA, Shaw GD (1995-10-20). "A sulfated peptide segment at the amino terminus of PSGL-1 is critical for P-selectin binding". Cell. 83 (2): 323–331. doi:10.1016/0092-8674(95)90173-6. ISSN 0092-8674. PMID 7585949.
  8. ^ Somers WS, Tang J, Shaw GD, Camphausen RT (2000-10-27). "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. ISSN 0092-8674. PMID 11081633.
  9. ^ Veldman GM, Bean KM, Cumming DA, Eddy RL, Sait SN, Shows TB (1995-07-07). "Genomic organization and chromosomal localization of the gene encoding human P-selectin glycoprotein ligand". The Journal of Biological Chemistry. 270 (27): 16470–16475. doi:10.1074/jbc.270.27.16470. ISSN 0021-9258. PMID 7541799.
  10. ^ "Entrez Gene: SELPLG selectin P ligand".
  11. ^ Li F, Wilkins PP, Crawley S, et al. (1996). "Post-translational modifications of recombinant P-selectin glycoprotein ligand-1 required for binding to P- and E-selectin". J. Biol. Chem. 271 (6): 3255–64. doi:10.1074/jbc.271.6.3255. PMID 8621728.
  12. ^ Wilkins PP, Moore KL, McEver RP, Cummings RD (1995). "Tyrosine sulfation of P-selectin glycoprotein ligand-1 is required for high affinity binding to P-selectin". J. Biol. Chem. 270 (39): 22677–80. doi:10.1074/jbc.270.39.22677. PMID 7559387.
  13. ^ Sako D, Comess KM, Barone KM, et al. (1995). "A sulfated peptide segment at the amino terminus of PSGL-1 is critical for P-selectin binding". Cell. 83 (2): 323–31. doi:10.1016/0092-8674(95)90173-6. PMID 7585949. S2CID 65420.
  14. ^ Pouyani T, Seed B (1995). "PSGL-1 recognition of P-selectin is controlled by a tyrosine sulfation consensus at the PSGL-1 amino terminus". Cell. 83 (2): 333–43. doi:10.1016/0092-8674(95)90174-4. PMID 7585950. S2CID 17480260.
  15. ^ 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. ISSN 1938-3673. PMID 19703898.
  16. ^ Zhang C, Zhang Y, Liu Y, Liu Y, Kageyama S, Shen XD, et al. (June 2017). "A Soluble Form of P Selectin Glycoprotein Ligand 1 Requires Signaling by Nuclear Factor Erythroid 2-Related Factor 2 to Protect Liver Transplant Endothelial Cells Against Ischemia-Reperfusion Injury". American Journal of Transplantation. 17 (6): 1462–1475. doi:10.1111/ajt.14159. PMC 5444987. PMID 27977895.
  17. ^ Sun X, Sammani S, Hufford M, Sun BL, Kempf CL, Camp SM, et al. (January 2023). "Targeting SELPLG/P-selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter". Pulmonary Circulation. 13 (1): e12206. doi:10.1002/pul2.12206. PMC 9982077. PMID 36873461.
  18. ^ Tinoco R, Carrette F, Barraza ML, Otero DC, Magaña J, Bosenberg MW, et al. (May 2016). "PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion". Immunity. 44 (5): 1190–203. doi:10.1016/j.immuni.2016.04.015. PMC 4908967. PMID 27192578.; Lay summary in: Kegel M (1 June 2016). "Immune Factor Seen to Control T-Cell Checkpoints Involved in Spread of Cancers and Infections". Immune-onocology News.
  19. ^ Johnston RJ, Su LJ, Pinckney J, Critton D, Boyer E, Krishnakumar A, et al. (October 2019). "VISTA is an acidic pH-selective ligand for PSGL-1". Nature. 574 (7779): 565–570. Bibcode:2019Natur.574..565J. doi:10.1038/s41586-019-1674-5. PMID 31645726.
  20. ^ Hope JL, Otero DC, Bae EA, Stairiker CJ, Palete AB, Faso HA, et al. (May 2023). "PSGL-1 attenuates early TCR signaling to suppress CD8+ T-cell progenitor differentiation and elicit terminal CD8+ Tcell exhaustion". Cell Reports. 42 (5): 112436. doi:10.1016/j.celrep.2023.112436. PMC 10403047. PMID 37115668.; Lay summary in: Sanford Burnham Prebys Medical Discovery Institute (4 May 2023). "Reviving exhausted T cells to tackle immunotherapy-resistant cancers". Medical Press.
  21. ^ DeRogatis JM, Viramontes KM, Neubert EN, Henriquez ML, Guerrero-Juarez CF, Tinoco R (2022-05-03). "Targeting the PSGL-1 Immune Checkpoint Promotes Immunity to PD-1-Resistant Melanoma". Cancer Immunology Research. 10 (5): 612–625. doi:10.1158/2326-6066.CIR-21-0690. ISSN 2326-6074. PMC 9064985. PMID 35303066.
  22. ^ Novobrantseva T, Manfra D, Ritter J, Razlog M, O'Nuallain B, Zafari M, et al. (August 2024). "Preclinical Efficacy of VTX-0811: A Humanized First-in-Class PSGL-1 mAb Targeting TAMs to Suppress Tumor Growth". Cancers. 16 (16): 2778. doi:10.3390/cancers16162778. PMC 11352552. PMID 39199551.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.