WASH has a critical role in NK cell cytotoxicity through Lck-mediated phosphorylation
WASH has a critical role in NK cell cytotoxicity through Lck-mediated phosphorylation
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WASH 通过 Lck 介导的磷酸化在 NK 细胞的细胞毒性中发挥关键作用
DOI：
10.1038/cddis.2016.212
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发表时间：
2016-07-01
影响因子：
9
通讯作者：
Fan, Z.
中科院分区：
文献类型：
--
作者：
Huang, L.;Zhu, P.;Fan, Z.
自然杀伤（NK）细胞是先天免疫系统的重要效应细胞，用于杀死某些病毒感染和转化的细胞。Wiskott-Aldrich综合征蛋白（WASP）和SCAR同源物（WASH）是WASP家族中参与细胞骨架重组的蛋白质，但其在淋巴细胞中的功能尚不清楚。在这里，我们证明了WASH对NK细胞的细胞毒性至关重要。发现WASH在NK细胞活化后与裂解颗粒共定位。敲低WASH表达实质上抑制了免疫突触的极化和溶解颗粒的释放，导致NK细胞细胞毒性的损害。更重要的是，我们的数据还定义了WASH功能的一个以前未被认识的机制，其中Src家族激酶Lck可以与WASH相互作用并诱导WASH磷酸化。酪氨酸残基Y141的突变，这里确定为WASH磷酸化的主要位点，部分阻断WASH酪氨酸磷酸化和NK细胞的细胞毒性。综上所述，这些观察结果表明，WASH具有通过Lck介导的Y141酪氨酸磷酸化调节NK细胞细胞毒性的关键作用。
Natural killer (NK) cells are important effector cells of the innate immune system to kill certain virus-infected and transformed cells. Wiskott-Aldrich Syndrome protein (WASP) and SCAR homolog (WASH) has been identified as a member of WASP family proteins implicated in regulating the cytoskeletal reorganization, yet little is known about its function in lymphocytes. Here we demonstrate that WASH is crucial for NK cell cytotoxicity. WASH was found to colocalize with lytic granules upon NK cell activation. Knockdown of WASH expression substantially inhibited polarization and release of lytic granules to the immune synapse, resulting in the impairment of NK cell cytotoxicity. More importantly, our data also define a previously unappreciated mechanism for WASH function, in which Src family kinase Lck can interact with WASH and induce WASH phosphorylation. Mutation of tyrosine residue Y141, identified here as the major site of WASH phosphorylation, partially blocked WASH tyrosine phosphorylation and NK cell cytotoxicity. Taken together, these observations suggest that WASH has a pivotal role for regulation of NK cell cytotoxicity through Lck-mediated Y141 tyrosine phosphorylation.