Hershkovitz Oren, Jivov Sergey, Bloushtain Noga, Zilka Alon, Landau Guy, Bar-Ilan Ahuva, Lichtenstein Rachel G, Campbell Kerry S, van Kuppevelt Toin H, Porgador Angel
The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, and the Cancer Research Center, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
Biochemistry. 2007 Jun 26;46(25):7426-36. doi: 10.1021/bi7000455. Epub 2007 May 31.
NKp44 is a natural cytotoxicity receptor expressed by human NK cells upon activation. In this study, we demonstrate that cell surface heparan sulfate proteoglycans (HSPGs), expressed by target cells, are involved in the recognition of tumor cells by NKp44. NKp44 showed heparan sulfate-dependent binding to tumor cells; this binding was partially blocked with an antibody to heparan sulfate. In addition, direct binding of NKp44 to heparin was observed, and soluble heparin/heparan sulfate enhanced the secretion of IFNgamma by NK92 cells activated with anti-NKp44 monoclonal antibody. Basic amino acids, predicted to constitute the putative heparin/heparan sulfate binding site of NKp44, were mutated. Tumor cell recognition of the mutated NKp44 proteins was significantly reduced and correlated with their lower recognition of heparin. We previously reported that NKp44 recognizes the hemagglutinin of influenza virus (IV). Nevertheless, the ability of the mutated NKp44 proteins to bind viral hemagglutinin expressed by IV-infected cells was not affected. Thus, we suggest that heparan sulfate epitope(s) are ligands/co-ligands of NKp44 and are involved in its tumor recognition ability.
NKp44是人类自然杀伤细胞（NK细胞）激活后表达的一种自然细胞毒性受体。在本研究中，我们证明靶细胞表达的细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）参与了NKp44对肿瘤细胞的识别。NKp44显示出对肿瘤细胞的硫酸乙酰肝素依赖性结合；这种结合被一种针对硫酸乙酰肝素的抗体部分阻断。此外，观察到NKp44与肝素的直接结合，并且可溶性肝素/硫酸乙酰肝素增强了用抗NKp44单克隆抗体激活的NK92细胞分泌γ干扰素（IFNγ）的能力。预测构成NKp44假定肝素/硫酸乙酰肝素结合位点的碱性氨基酸发生了突变。突变的NKp44蛋白对肿瘤细胞的识别显著降低，并且与其对肝素的较低识别相关。我们之前报道过NKp44识别流感病毒（IV）的血凝素。然而，突变的NKp44蛋白结合IV感染细胞表达的病毒血凝素的能力未受影响。因此，我们认为硫酸乙酰肝素表位是NKp44的配体/共配体，并参与其肿瘤识别能力。
