Phosphorylation of the myosin IIA tailpiece regulates single myosin IIA molecule association with lytic granules to promote NK-cell cytotoxicity.
Phosphorylation of the myosin IIA tailpiece regulates single myosin IIA molecule association with lytic granules to promote NK-cell cytotoxicity.
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DOI：
10.1182/blood-2011-03-344846
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发表时间：
2011-11
期刊：
影响因子：
20.3
通讯作者：
Keri B. Sanborn;E. Mace;Gregory D Rak;A. Difeo;J. Martignetti;A. Pecci;J. Bussel;R. Favier;J. Orange
中科院分区：
文献类型：
--
作者：
Keri B. Sanborn;E. Mace;Gregory D Rak;A. Difeo;J. Martignetti;A. Pecci;J. Bussel;R. Favier;J. Orange
自然杀伤（NK）细胞是先天免疫淋巴细胞，其提供对病毒感染和转化细胞的关键防御。NK细胞的细胞毒性需要形成富含F-肌动蛋白的免疫突触（IS），以及含有穿孔素的裂解颗粒向IS的极化和在IS分泌其内容物。据报道，以前，NK细胞的细胞毒性需要非肌肉肌球蛋白IIA功能和颗粒相关的肌球蛋白IIA介导的颗粒与F-肌动蛋白在IS的相互作用。在本研究中，我们评估了肌球蛋白IIA与溶解颗粒的关联性质。使用肌球蛋白IIA突变患者的NK细胞，我们发现非螺旋尾片段是NK细胞细胞毒性和颗粒相关肌球蛋白IIA磷酸化所需的。超分辨率成像技术表明，单个肌球蛋白IIA分子通过非螺旋尾片段与NK细胞裂解颗粒相关联。该连接需要尾片段中的肌球蛋白IIA在残基丝氨酸1943（S1943）处的磷酸化。这定义了肌球蛋白II功能的一种新机制，其中肌球蛋白IIA可以充当单分子肌动蛋白马达，通过尾依赖性磷酸化将颗粒作为货物，用于执行人NK细胞细胞毒性中的前最终步骤。
Natural killer (NK) cells are innate immune lymphocytes that provide critical defense against virally infected and transformed cells. NK-cell cytotoxicity requires the formation of an F-actin rich immunologic synapse (IS), as well as the polarization of perforin-containing lytic granules to the IS and secretion of their contents at the IS. It was reported previously that NK-cell cytotoxicity requires nonmuscle myosin IIA function and that granule-associated myosin IIA mediates the interaction of granules with F-actin at the IS. In the present study, we evaluate the nature of the association of myosin IIA with lytic granules. Using NK cells from patients with mutations in myosin IIA, we found that the nonhelical tailpiece is required for NK-cell cytotoxicity and for the phosphorylation of granule-associated myosin IIA. Ultra-resolution imaging techniques demonstrated that single myosin IIA molecules associate with NK-cell lytic granules via the nonhelical tailpiece. Phosphorylation of myosin IIA at residue serine 1943 (S1943) in the tailpiece is needed for this linkage. This defines a novel mechanism for myosin II function, in which myosin IIA can act as a single-molecule actin motor, claiming granules as cargo through tail-dependent phosphorylation for the execution of a pre-final step in human NK-cell cytotoxicity.