Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada.
Immunity. 2012 Jun 29;36(6):974-85. doi: 10.1016/j.immuni.2012.03.023. Epub 2012 Jun 7.
The adaptor SAP, mutated in X-linked lymphoproliferative disease, has critical roles in multiple immune cell types. Among these, SAP is essential for the ability of natural killer (NK) cells to eliminate abnormal hematopoietic cells. Herein, we elucidated the molecular and cellular bases of this activity. SAP enhanced NK cell responsiveness by a dual molecular mechanism. It coupled SLAM family receptors to the kinase Fyn, which triggered the exchange factor Vav-1 and augmented NK cell activation. SAP also prevented the inhibitory function of SLAM family receptors. This effect was Fyn independent and correlated with uncoupling of SLAM family receptors from the lipid phosphatase SHIP-1. Both mechanisms cooperated to enable conjugate formation with target cells and to stimulate cytotoxicity and cytokine secretion by NK cells. These data showed that SAP secures NK cell activation by a dichotomous molecular mechanism, which is required for conjugate formation. These findings may have implications for the role of SAP in other immune cell types.
衔接蛋白 SAP 在 X 连锁淋巴组织增生性疾病中发生突变，在多种免疫细胞类型中发挥关键作用。在这些细胞中，SAP 对于自然杀伤 (NK) 细胞消除异常造血细胞的能力是必需的。在此，我们阐明了这种活性的分子和细胞基础。SAP 通过双重分子机制增强 NK 细胞的反应性。它将 SLAM 家族受体与激酶 Fyn 偶联，触发了交换因子 Vav-1，并增强了 NK 细胞的激活。SAP 还防止了 SLAM 家族受体的抑制功能。这种效应不依赖于 Fyn，与 SLAM 家族受体与脂质磷酸酶 SHIP-1 解偶联相关。这两种机制共同促进与靶细胞的共轭形成，并刺激 NK 细胞的细胞毒性和细胞因子分泌。这些数据表明，SAP 通过二分体分子机制来确保 NK 细胞的激活，这对于共轭形成是必需的。这些发现可能对 SAP 在其他免疫细胞类型中的作用具有重要意义。
