Immunology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Blood. 2011 Nov 24;118(22):5862-71. doi: 10.1182/blood-2011-03-344846.
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.
自然杀伤 (NK) 细胞是先天免疫淋巴细胞，对病毒感染和转化细胞提供关键防御。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)，以及将含有穿孔素的溶酶体颗粒向 IS 极化和在 IS 处分泌其内容物。先前有报道称，NK 细胞的细胞毒性需要非肌肉肌球蛋白 IIA 的功能，并且颗粒相关的肌球蛋白 IIA 介导颗粒与 IS 处的 F-肌动蛋白的相互作用。在本研究中，我们评估了肌球蛋白 IIA 与溶酶体颗粒的关联的性质。使用来自肌球蛋白 IIA 突变患者的 NK 细胞，我们发现非螺旋尾部片段对于 NK 细胞的细胞毒性和颗粒相关肌球蛋白 IIA 的磷酸化是必需的。超分辨率成像技术表明，单个肌球蛋白 IIA 分子通过非螺旋尾部片段与 NK 细胞的溶酶体颗粒相关联。尾部残基丝氨酸 1943 (S1943) 上的肌球蛋白 IIA 磷酸化对于这种连接是必需的。这定义了肌球蛋白 II 功能的一种新机制，其中肌球蛋白 IIA 可以作为单个分子肌动蛋白马达，通过尾部依赖性磷酸化来主张颗粒作为货物，以执行人 NK 细胞细胞毒性的最终前步骤。
