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Brusilovsky M , Cordoba M , Rosental B , Hershkovitz O , Andrake MD , Pecherskaya A , Einarson MB , Zhou Y , Braiman A , Campbell KS , Porgador A
Genome-wide siRNA screen reveals a new cellular partner of NK cell receptor KIR2DL4: heparan sulfate directly modulates KIR2DL4-mediated responses
J Immunol. 2013 Nov 15;191(10) :5256-67
PMID: 24127555    PMCID: PMC3836631   
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KIR2DL4 (CD158d) is a distinct member of the killer cell Ig-like receptor (KIR) family in human NK cells that can induce cytokine production and cytolytic activity in resting NK cells. Soluble HLA-G, normally expressed only by fetal-derived trophoblast cells, was reported to be a ligand for KIR2DL4; however, KIR2DL4 expression is not restricted to the placenta and can be found in CD56(high) subset of peripheral blood NK cells. We demonstrated that KIR2DL4 can interact with alternative ligand(s), expressed by cells of epithelial or fibroblast origin. A genome-wide high-throughput siRNA screen revealed that KIR2DL4 recognition of cell-surface ligand(s) is directly regulated by heparan sulfate (HS) glucosamine 3-O-sulfotransferase 3B1 (HS3ST3B1). KIR2DL4 was found to directly interact with HS/heparin, and the D0 domain of KIR2DL4 was essential for this interaction. Accordingly, exogenous HS/heparin can regulate cytokine production by KIR2DL4-expressing NK cells and HEK293T cells (HEK293T-2DL4), and induces differential localization of KIR2DL4 to rab5(+) and rab7(+) endosomes, thus leading to downregulation of cytokine production and degradation of the receptor. Furthermore, we showed that intimate interaction of syndecan-4 (SDC4) HS proteoglycan (HSPG) and KIR2DL4 directly affects receptor endocytosis and membrane trafficking.
Brusilovsky, Michael Cordoba, Moti Rosental, Benyamin Hershkovitz, Oren Andrake, Mark D Pecherskaya, Anna Einarson, Margret B Zhou, Yan Braiman, Alex Campbell, Kerry S Porgador, Angel CA06927/CA/NCI NIH HHS/United States CA083859/CA/NCI NIH HHS/United States CA100226/CA/NCI NIH HHS/United States R01 CA083859/CA/NCI NIH HHS/United States R01 CA100226/CA/NCI NIH HHS/United States R56 CA100226/CA/NCI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States J Immunol. 2013 Nov 15;191(10):5256-67. doi: 10.4049/jimmunol.1302079. Epub 2013 Oct 14.