L-selectin

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SELL
Protein SELL PDB 1KJB.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSELL, CD62L, LAM1, LECAM1, LEU8, LNHR, LSEL, LYAM1, PLNHR, TQ1, selectin L
External IDsOMIM: 153240 MGI: 98279 HomoloGene: 539 GeneCards: SELL
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000655

NM_001164059
NM_011346

RefSeq (protein)

NP_000646

NP_001157531
NP_035476

Location (UCSC)Chr 1: 169.69 – 169.71 MbChr 1: 163.89 – 163.91 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes and the preimplantation embryo. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups containing a Sialyl LewisX (sLeX) determinant.[5] L-selectin plays an important role in both the innate and adaptive immune responses by facilitating leukocyte-endothelial cell adhesion events.[6] 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.[6] 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.[7]

L-selectin is composed of multiple structural regions: an N-terminus C-type lectin domain, an adjacent epidermal growth factor-like domain, two to the consensus repeat units homologous to those found in C3/C4-binding proteins, an extracellular cleavage site, a short transmembrane domain, and a cytoplasmic tail. It is cleaved by ADAM17.[6][8]

Ligands

Expression

L-selectin is expressed constitutively on most circulating leukocytes.[6] Over time, these molecules are released through the process of ectodomain shedding and are replaced by newly synthesized L-selectin proteins. Ectodomain shedding is largely accomplished through cleavage by ADAM17.

L-selectin is expressed on naive T cells and is rapidly shed following T cell priming.[6] L-selectin expression is re-activated in cytotoxic T cells once they exit the lymph node.  Mature central memory T cells express L-selectin while effector memory cells do not. L-selectin is also expressed by naive B cells, with the loss of L-selectin distinguishing activated B cells destined to differentiate to antibody-secreting cells

L-selectin is expressed on circulating neutrophils and is shed following neutrophil priming.[6] Expression of L-selectin in neutrophils decreases with neutrophil aging. Classical monocytes express high levels of L-selectin while in circulation. Shedding of L-selectin from monocytes occurs during trans-endothelial migration.

L-selectin expression is also observed on oocytes and early-stage embryos. Blastocysts express L-selectin following, but not prior to emergence from the zona pellucida. An increase in L-selectin expression is observed when both the blastocyst and cytotrophoblast attach to the endometrium.  L-selectin expression decreases by the 17th week of pregnancy, and remains low or non-existent until term (2017).[7]

Function

Lymphocytes

L-selectin acts as a "homing receptor" for lymphocytes to enter secondary lymphoid tissues via high endothelial venules. Ligands present on endothelial cells will bind to lymphocytes expressing L-selectin, slowing lymphocyte trafficking through the blood, and facilitating entry into a secondary lymphoid organ at that point.[9] The receptor is commonly found on the cell surfaces of T cells. Naive T-lymphocytes, which have not yet encountered their specific antigen, need to enter secondary lymph nodes to encounter their antigen. Central memory T-lymphocytes, which have encountered antigen, express L-selectin to localize in secondary lymphoid organs. Here they reside ready to proliferate upon re-encountering antigen. Effector memory T-lymphocytes do not express L-selectin, as they circulate in the periphery and have immediate effector functions upon encountering antigen. High expression of L-selectin on human bone marrow progenitor cells is an early sign of cells becoming committed to lymphoid differentiation.[10]

Neutrophils and Monocytes

Similar to its role in homing lymphocytes to secondary lymphoid tissues, L-selectin expressed on the surface of monocytes and neutrophils is essential for facilitating the first stage of adhesion to venule epithelial cells (known as the “rolling stage”).[6][5] Adhesion to activated epithelial cells is a critical step in the immune response as it allows these immune cells to emigrate from the bloodstream into inflamed tissue. Prolonged rolling and transmigration of neutrophils can trigger shedding of L-selectin from the neutrophil plasma membrane.[5] The membrane-bound fragment left behind following cleavage of L-selectin has also been suggested to play a critical role in the interstitial chemotaxis of neutrophils along a cytokine gradient.[6] L-selectin shedding also occurs in monocytes; however, in these cells shedding is triggered only during trans-endothelial and not by earlier stages of the adhesion process.[6] The specific shedding of L-selectin from the leading migratory fronts of transmigrating monocytes suggests that this process plays a role in facilitating the directional migration of these cells (2019).[6]

Embryo

L-selectin is also present on the surface of human embryo trophoblasts prior to implantation into the uterus. Similar to its function in lymphocytes, L-selectin acts as a receptor to facilitate adhesion of the embryo to the site of invasion on the surface epithelium of the uterine endometrium. The embryo secretes human chorionic gonadotropin (hCG), which downregulates anti-adhesion factor, MUC-1, located on the uterine epithelium at the site of invasion. Removal of MUC-1 exposes the oligosaccharide ligands of the uterine epithelium, thus allowing binding by the L-selectin receptor of the trophoblast cell, followed by embryo adhesion and invasion.[11]

Clinical Significance

Human Immunodeficiency Virus (HIV)

L-selectin expressed on CD4 T lymphocytes has been implicated in mediating adhesion and entry of HIV. L-selectin binds gp120, one of the many glycans present on the HIV envelope. This binding allows for rolling adhesion to T cells and thus facilitates the binding of HIV to its target receptors.[12] Infection of the cell triggers shedding of L-selectin. The loss of L-selectin likely aids in the release of new virus from the cell.

Abnormal Pregnancy and infertility

The binding of L-selectin to its ligands plays an important role in embryo implantation during human pregnancy. Deficiency epithelial expression of L-selectin ligands has been associated with infertility, while increased expression has been implicated in ectopic pregnancies[7]

Cancer

The adhesive properties of L-selectin have been shown to contribute to cancer progression. L-selectin interactions participate in trafficking of chronic lymphocytic leukemia cells to the lymph nodes where they are able to proliferate and evolve. Additionally, L-selectin interactions may play a role in metastasis.[13]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000188404 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026581 - 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. ^ a b c Ivetic A (March 2018). "A head-to-tail view of L-selectin and its impact on neutrophil behaviour". Cell and Tissue Research. 371 (3): 437–453. doi:10.1007/s00441-017-2774-x. PMC 5820395. PMID 29353325.
  6. ^ a b c d e f g h i j Ivetic A, Hoskins Green HL, Hart SJ (2019-05-14). "L-selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling". Frontiers in Immunology. 10: 1068. doi:10.3389/fimmu.2019.01068. PMC 6527602. PMID 31139190.
  7. ^ a b c Feng Y, Ma X, Deng L, Yao B, Xiong Y, Wu Y, et al. (May 2017). "Role of selectins and their ligands in human implantation stage". Glycobiology. 27 (5): 385–391. doi:10.1093/glycob/cwx009. PMID 28115423.
  8. ^ Tvaroška I, Selvaraj C, Koča J (June 2020). "Selectins-The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules-A Review". Molecules. 25 (12): 2835. doi:10.3390/molecules25122835. PMC 7355470. PMID 32575485.
  9. ^ Robbins SL, Cotran RS, Kumar V, Collins T (1998). Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company. ISBN 0-7216-7335-X.
  10. ^ Kohn LA, Hao QL, Sasidharan R, Parekh C, Ge S, Zhu Y, et al. (October 2012). "Lymphoid priming in human bone marrow begins before expression of CD10 with upregulation of L-selectin". Nature Immunology. 13 (10): 963–971. doi:10.1038/ni.2405. PMC 3448017. PMID 22941246.
  11. ^ James JL, Carter AM, Chamley LW (May 2012). "Human placentation from nidation to 5 weeks of gestation. Part I: What do we know about formative placental development following implantation?". Placenta. 33 (5): 327–334. doi:10.1016/j.placenta.2012.01.020. PMID 22374510.
  12. ^ Segura J, He B, Ireland J, Zou Z, Shen T, Roth G, Sun PD (2021-09-29). "The Role of L-Selectin in HIV Infection". Frontiers in Microbiology. 12: 725741. doi:10.3389/fmicb.2021.725741. PMC 8511817. PMID 34659153.
  13. ^ Natoni A, Macauley MS, O'Dwyer ME (2016). "Targeting Selectins and Their Ligands in Cancer". Frontiers in Oncology. 6: 93. doi:10.3389/fonc.2016.00093. PMC 4834419. PMID 27148485.

External links

Further reading

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