Saborit-Villarroya Ifigenia, Martinez-Barriocanal Agueda, Oliver-Vila Irene, Engel Pablo, Sayos Joan, Martin Margarita
Immunoreceptors group, Institut d'Investigació August Pi i Sunyer (IDIBAPS), Immunology Unit, Department of Cellular Biology and Pathology, Medical School, University of Barcelona, Barcelona, Spain.
Mol Immunol. 2008 Jul;45(12):3446-53. doi: 10.1016/j.molimm.2008.03.021. Epub 2008 May 13.
Natural killer (NK) cell cytotoxicity requires triggering of activation receptors over inhibitory receptors. CD244, a member of CD150 receptor family, positively regulates NK-mediated lyses by activating an intracellular multiproteic signaling network that involves the adaptors X-linked lymphoproliferative gene product SAP and 3BP2. However, the exact mechanisms used by 3BP2 to enhance CD244-mediated cytotoxicity are still not fully understood. Here using the human NK cell line YT-overexpressing 3BP2, we found that the adaptor increases CD244, PI3K, and Vav phosphorylation upon CD244 engagement. The use of enzymatic inhibitors revealed that 3BP2-dependent cytolysis enhancement was PKC-dependent and PI3K-ERK independent. Furthermore, 3BP2 overexpression enhanced PKC delta phosphorylation. SAP knockdown expression inhibited PKC delta activation, indicating that the activating role played by 3BP2 depends upon the presence of SAP. In conclusion, our data show that 3BP2 acts downstream of SAP, increases CD244 phosphorylation and links the receptor with PI3K, Vav, PLC gamma, and PKC downstream events in order to achieve maximum NK killing function.
自然杀伤（NK）细胞的细胞毒性需要激活受体触发抑制性受体。CD244是CD150受体家族的成员，通过激活一个涉及衔接蛋白X连锁淋巴增殖性基因产物SAP和3BP2的细胞内多蛋白信号网络，正向调节NK介导的细胞溶解。然而，3BP2增强CD244介导的细胞毒性的确切机制仍未完全了解。在这里，我们使用过表达3BP2的人NK细胞系YT，发现该衔接蛋白在CD244结合后增加CD244、PI3K和Vav的磷酸化。使用酶抑制剂显示，3BP2依赖的细胞溶解增强是PKC依赖的，且不依赖于PI3K-ERK。此外，3BP2过表达增强了PKCδ的磷酸化。SAP基因敲低表达抑制了PKCδ的激活，表明3BP2发挥的激活作用取决于SAP的存在。总之，我们的数据表明，3BP2在SAP下游起作用，增加CD244磷酸化，并将该受体与PI3K、Vav、PLCγ和PKC下游事件联系起来，以实现最大的NK杀伤功能。
