SELPLG

Official Full Name

selectin P ligand

Organism

Homo sapiens

GeneID

6404

Background

This gene encodes a glycoprotein that functions as a high affinity counter-receptor for the cell adhesion molecules P-, E- and L- selectin expressed on myeloid cells and stimulated T lymphocytes. As such, this protein plays a critical role in leukocyte trafficking during inflammation by tethering of leukocytes to activated platelets or endothelia expressing selectins. This protein requires two post-translational modifications, tyrosine sulfation and the addition of the sialyl Lewis x tetrasaccharide (sLex) to its O-linked glycans, for its high-affinity binding activity. Aberrant expression of this gene and polymorphisms in this gene are associated with defects in the innate and adaptive immune response. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2011]

Synonyms

CLA; CD162; PSGL1; PSGL-1;

Protein Sequence

MPLQLLLLLILLGPGNSLQLWDTWADEAEKALGPLLARDRRQATEYEYLDYDFLPETEPPEMLRNSTDTTPLTGPGTPESTTVEPAARRSTGLDAGGAVTELTTELANMGNLSTDSAAMEIQTTQPAATEAQTTQPVPTEAQTTPLAATEAQTTRLTATEAQTTPLAATEAQTTPPAATEAQTTQPTGLEAQTTAPAAMEAQTTAPAAMEAQTTPPAAMEAQTTQTTAMEAQTTAPEATEAQTTQPTATEAQTTPLAAMEALSTEPSATEALSMEPTTKRGLFIPFSVSSVTHKGIPMAASNLSVNYPVGAPDHISVKQCLLAILILALVATIFFVCTVVLAVRLSRKGHMYPVRNYSPTEMVCISSLLPDGGEGPSATANGGLSKAKSPGLTPEPREDREGDDLTLHSFLP

Open

Disease

Allergic/hypersensitivity disorder, Asthma, Chronic obstructive pulmonary disease, Myocardial infarction, Psoriatic arthritis

Approved Drug

Clinical Trial Drug

4 +

Discontinued Drug

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Detailed Information

The SELPLG gene is located on chromosome 12q24.31 and spans about 14.2 kb, containing three exons. Its mRNA transcript is approximately 1.8 kb and encodes P-selectin glycoprotein ligand-1 (PSGL-1, also known as CD162), a type I transmembrane glycoprotein of 402 amino acids. While its predicted molecular weight is about 120 kDa, extensive glycosylation increases its apparent size to over 240 kDa. Structurally, PSGL-1 features an extracellular mucin-like domain rich in serine and threonine with heavy O-linked glycosylation, three sulfated tyrosine residues at the N-terminus, and a short cytoplasmic tail of 69 amino acids. This design enables PSGL-1 to function as a high-affinity counter-receptor for selectins.

Expression and Regulation

PSGL-1 expression is cell-type specific, restricted mainly to myeloid cells (neutrophils, monocytes, dendritic cells) and activated lymphocytes. During hematopoietic differentiation, expression increases, reaching the highest levels in mature neutrophils. Transcription is regulated by PU.1 and C/EBP, key myeloid transcription factors, and modulated by inflammatory signals. TNF-α and LPS enhance expression in monocytes, while IL-4 suppresses it, reflecting the immune microenvironment’s fine-tuned control.

Post-Translational Modifications

PSGL-1 function requires two essential modifications. First, tyrosine sulfation of residues Tyr46, Tyr48, and Tyr51 by TPST provides critical binding sites for P-selectin. Second, specific glycosylation catalyzed by FUT7 and sialyltransferases produces sialyl Lewis X (sLeˣ) structures at the termini of O-glycans. These modifications together form the molecular basis for selectin recognition, combining electrostatic interactions from sulfated tyrosines and carbohydrate specificity from sLeˣ. Defects in either step abolish function.

Biological Roles

PSGL-1’s central role is mediating leukocyte tethering and rolling on activated endothelium or platelets during inflammation. It binds sequentially to P- and E-selectins, supporting rolling under shear stress and facilitating stable adhesion through integrins. Its affinity for P-selectin is much higher than for E-selectin, explaining its dominant role in platelet-mediated leukocyte capture. The binding involves multivalent interactions between the sulfated N-terminus and selectin lectin domains, reinforced by mucin glycan engagement with EGF-like domains, yielding strong adhesion even under hemodynamic conditions.

PSGL-1 also transduces signals. Upon ligation, its cytoplasmic tail links to the actin cytoskeleton via adaptor proteins such as moesin and activates kinases including Lyn and Syk. This leads to integrin activation, cytoskeletal remodeling, and inflammatory gene expression. In neutrophils, PSGL-1 engagement activates MAPK and NF-κB pathways to drive cytokine secretion, while in T cells it modulates TCR signaling and Th1/Th2 balance. Additionally, PSGL-1 acts as a receptor for enterovirus 71 (EV71), with viral capsid protein VP1 binding its sulfated tyrosines to mediate entry.

Disease Associations

PSGL-1 contributes to multiple inflammatory diseases. In ARDS, endothelial P-selectin mediates neutrophil sequestration via PSGL-1, promoting alveolar damage; blocking PSGL-1 reduces injury in models. In rheumatoid arthritis, PSGL-1 expression on synovial leukocytes correlates with disease activity. In atherosclerosis, PSGL-1 supports monocyte recruitment, platelet-monocyte aggregate formation, and neutrophil extracellular trap generation, with knockout studies confirming its pro-atherogenic role.

It also participates in host defense, facilitating bacterial clearance in sepsis and neutrophil recruitment in fungal infections, though persistent activation may contribute to immune exhaustion in late sepsis. In tumors, PSGL-1 expression on myeloid-derived suppressor cells or leukemia cells can promote immune evasion, metastasis, or chemotherapy resistance, highlighting its role in shaping the tumor microenvironment.

Therapeutic Strategies and Challenges

Targeting PSGL-1 has been explored to disrupt pathological adhesion. Antibodies such as KPL-1 and recombinant fusion proteins like rPSGL-Ig block selectin binding and have shown benefits in experimental models of ischemia, arthritis, and atherosclerosis. However, clinical outcomes have been variable, as seen in trials for myocardial infarction, where endpoints were not met.

Small-molecule antagonists face challenges due to the broad binding interface, though sulfated tyrosine mimetics and polysaccharide derivatives have been investigated. Aptamers have emerged as promising tools, with some showing high affinity and selectivity for activated leukocyte PSGL-1, enabling targeted inhibition of inflammatory cell recruitment. Aptamer-drug conjugates further suggest potential for localized delivery of anti-inflammatory agents.

Future work must address tissue-specific delivery, selective modulation of adhesion versus signaling functions, and combination strategies targeting multiple adhesion pathways to overcome redundancy.

Reference

Murakami T, Ono A. Roles of Virion-Incorporated CD162 (PSGL-1), CD43, and CD44 in HIV-1 Infection of T Cells. Viruses. 2021 Sep 26;13(10):1935.
Zarbock A, Müller H, Kuwano Y, et al. PSGL-1-dependent myeloid leukocyte activation. J Leukoc Biol. 2009 Nov;86(5):1119-24.

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