title: Regulation of natural cytotoxicity receptors by heparan sulfate proteoglycans in -cis: A lesson from NKp44.
abstract: NKp44 (NCR2) is a distinct member of natural cytotoxicity receptors (NCRs) family that can induce cytokine production and cytolytic activity in human NK cells. Heparan sulfate proteoglycans (HSPGs) are differentially expressed in various normal and cancerous tissues. HSPGs were reported to serve as ligands/co-ligands for NKp44 and other NCRs. However, HSPG expression is not restricted to either group and can be found also in NK cells. Our current study reveals that NKp44 function can be modulated through interactions with HSPGs on NK cells themselves in -cis rather than on target cells in -trans. The intimate interaction of NKp44 and the NK cell-associated HSPG syndecan-4 (SDC4) in -cis can directly regulate membrane distribution of NKp44 and constitutively dampens the triggering of the receptor. We further demonstrate, that the disruption of NKp44 and SDC4 interaction releases the receptor to engage with its ligands in -trans and therefore enhances NKp44 activation potential and NK cell functional response.
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Brusilovsky
authors.forename: Olga
authors.initials: O
authors.lastname: Radinsky
authors.forename: Limor
authors.initials: L
authors.lastname: Cohen
authors.forename: Rami
authors.initials: R
authors.lastname: Yossef
authors.forename: Avishai
authors.initials: A
authors.lastname: Shemesh
authors.forename: Alex
authors.initials: A
authors.lastname: Braiman
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.forename: Angel
authors.initials: A
authors.lastname: Porgador
mesh_terms: D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology; D053671:Syndecan-4 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D019812:Heparan Sulfate Proteoglycans; C112837:NCR2 protein, human; D055629:Natural Cytotoxicity Triggering Receptor 2; D011971:Receptors, Immunologic; C508304:SDC4 protein, human; D053671:Syndecan-4
keywords: Heparan sulfate; Heparan sulfate proteoglycans; Immune regulation; NCR2; NK cell activation; NKp44; Natural cytotoxicity receptors; Syndecan 4