P-selectin glycoprotein ligand-1

Last updated

SELPLG
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SELPLG , CD162, CLA, PSGL-1, PSGL1, selectin P ligand
External IDs OMIM: 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 Mb Chr 5: 113.96 – 113.97 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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

Contents

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]

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. [7] [8]

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: [9] [10] [11] [12]

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.[ citation needed ]

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. [13] [14]

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. [15]

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). [16]

In mice, PSGL-1 seems to facilitate T cell exhaustion in tumors. [17] 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. [18] 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. [19]

Related Research Articles

Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.

In biochemistry, tyrosine sulfation is a posttranslational modification where a sulfate group is added to a tyrosine residue of a protein molecule. Secreted proteins and extracellular parts of membrane proteins that pass through the Golgi apparatus may be sulfated. Sulfation was first discovered by Bettelheim in bovine fibrinopeptide B in 1954 and later found to be present in animals and plants but not in prokaryotes or in yeast.

<span class="mw-page-title-main">Selectin</span> Family of cell adhesion molecules

The selectins are a family of cell adhesion molecules. All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.

<span class="mw-page-title-main">CD44</span> Cell-surface glycoprotein

The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on chromosome 11. CD44 has been referred to as HCAM, Pgp-1, Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.

<span class="mw-page-title-main">P-selectin</span> Type-1 transmembrane protein

P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene.

<span class="mw-page-title-main">ICAM-1</span> Mammalian protein found in Homo sapiens

ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.

<span class="mw-page-title-main">L-selectin</span> Mammalian protein found in Homo sapiens

L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. It is coded for in the human by the SELL gene. L-selectin belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups containing a Sialyl LewisX (sLeX) determinant. L-selectin plays an important role in both the innate and adaptive immune responses by facilitating leukocyte-endothelial cell adhesion events. These tethering interactions are essential for the trafficking of monocytes and neutrophils into inflamed tissue as well as the homing of lymphocytes to secondary lymphoid organs. L-selectin is also expressed by lymphoid primed hematopoietic stem cells and may participate in the migration of these stem cells to the primary lymphoid organs. In addition to its function in the immune response, L-selectin is expressed on embryonic cells and facilitates the attachment of the blastocyst to the endometrial endothelium during human embryo implantation.

<span class="mw-page-title-main">E-selectin</span> Mammalian protein found in Homo sapiens

E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.

Sialyl-Lewis <sup>X</sup> Chemical compound

Sialyl LewisX (sLeX), also known as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1), is a tetrasaccharide carbohydrate which is usually attached to O-glycans on the surface of cells. It is known to play a vital role in cell-to-cell recognition processes. It is also the means by which an egg attracts sperm; first, to stick to it, then bond with it and eventually form a zygote.

<span class="mw-page-title-main">Leukocyte extravasation</span> Movement of white blood cells out of blood vessels and towards the inflamed site

In immunology, leukocyte extravasation is the movement of leukocytes out of the circulatory system (extravasation) and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.

<span class="mw-page-title-main">CD47</span> Protein-coding gene in humans

CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.

<span class="mw-page-title-main">F11 receptor</span> Protein-coding gene in humans

Junctional adhesion molecule A is a protein that in humans is encoded by the F11R gene. It has also been designated as CD321.

<span class="mw-page-title-main">Signal-regulatory protein alpha</span> Protein-coding gene in the species Homo sapiens

Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.

<span class="mw-page-title-main">GCNT1</span> Protein-coding gene in the species Homo sapiens

Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the GCNT1 gene.

<span class="mw-page-title-main">CD226</span> Protein found in humans

CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.

<span class="mw-page-title-main">CHST2</span> Protein-coding gene in the species Homo sapiens

Carbohydrate sulfotransferase 2 is an enzyme that in humans is encoded by the CHST2 gene.

<span class="mw-page-title-main">CHST4</span> Protein-coding gene in the species Homo sapiens

Carbohydrate sulfotransferase 4 is an enzyme that in humans is encoded by the CHST4 gene.

<span class="mw-page-title-main">CHST1</span> Protein-coding gene in the species Homo sapiens

Carbohydrate sulfotransferase 1 is an enzyme that in humans is encoded by the CHST1 gene.

<span class="mw-page-title-main">ADAM28</span> Protein-coding gene in humans

Disintegrin and metalloproteinase domain-containing protein 28 is an enzyme that in humans is encoded by the ADAM28 gene.

A catch bond is a type of noncovalent bond whose dissociation lifetime increases with tensile force applied to the bond. Normally, bond lifetimes are expected to diminish with force. In the case of catch bonds, the lifetime of the bond actually increases up to a maximum before it decreases like in a normal bond. Catch bonds work in a way that is conceptually similar to that of a Chinese finger trap. While catch bonds are strengthened by an increase in force, the force increase is not necessary for the bond to work. Catch bonds were suspected for many years to play a role in the rolling of leukocytes, being strong enough to roll in presence of high forces caused by high shear stresses, while avoiding getting stuck in capillaries where the fluid flow, and therefore shear stress, is low. The existence of catch bonds was debated for many years until strong evidence of their existence was found in bacteria. Definite proof of their existence came shortly thereafter in leukocytes.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000110876 – Ensembl, May 2017
  2. 1 2 3 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. ↑ 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.
  8. ↑ "Entrez Gene: SELPLG selectin P ligand".
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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

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