Nanoscale Dynamism of Actin Enables Secretory Function in Cytolytic Cells.
Nanoscale Dynamism of Actin Enables Secretory Function in Cytolytic Cells.
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DOI：
10.1016/j.cub.2017.12.044
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发表时间：
2018-02-19
期刊：
影响因子：
--
通讯作者：
Orange JS
中科院分区：
文献类型：
--
作者：
Carisey AF;Mace EM;Saeed MB;Davis DM;Orange JS
自然杀伤（NK）细胞是先天性免疫效应细胞，通过形成免疫突触裂解病毒感染和致瘤细胞。肌动蛋白在溶解性免疫突触的重塑是细胞毒性功能的多个方面的关键要求。激活受体和整合素信号传导导致肌动蛋白的调节性周转和重塑，这是粘附、持续受体信号传导和最终胞吐所需的。NK细胞在弥漫性肌动蛋白网络的低密度区域经历溶解性颗粒胞吐作用。虽然这些要求已经得到了很好的证明，无论是突触肌动蛋白的动态调节，也不是它的具体功能，然而，已确定在纳米级水平。在这里，活细胞超分辨率显微镜显示纳米级丝状肌动蛋白动态NK细胞溶解颗粒分泌。在细胞铺展之后，免疫突触处的分支肌动蛋白网络的总体内容随着时间的推移是稳定的，并且包含分支肌动蛋白纤维和离散的肌动蛋白灶。在溶细胞性T细胞中产生类似的肌动蛋白结构，尽管时间尺度与NK细胞不同。单个细丝位移导致随机间隙形成和消失，这与溶解颗粒的定位无关。肌动蛋白动力学依赖于Arp 2/3介导的分支网络形成和肌球蛋白IIA产生的收缩性。重要的是，小分子抑制剂的使用表明，肌动蛋白动力学是颗粒分泌的最终需要。因此，我们描述了一个纳米级的肌动蛋白纤维重排产生的复杂的肌动蛋白结构，使溶解颗粒分泌的要求。F-肌动蛋白在CTL和NK细胞的免疫突触处形成容许网络NK细胞的成熟IS的肌动蛋白网格由Arp 2/3分支活性形成纳米级肌动蛋白动力学是允许脱粒所必需的纳米级动力学是调节细胞毒性功能的新机会自然杀伤细胞通过将溶解颗粒释放到免疫突触间隙中来消除靶细胞。脱粒通过NK细胞的皮质肌动蛋白网内的大小允许的间隙发生。这种Arp 2/3介导的细胞骨架经历了产生清除和实现细胞毒性功能所需的恒定纳米级动力学。
Natural killer (NK) cells are innate immune effectors that lyse virally infected and tumorigenic cells through the formation of an immunological synapse. Actin remodeling at the lytic immunological synapse is a critical requirement for multiple facets of cytotoxic function. Activating receptor and integrin signaling leads to the regulated turnover and remodeling of actin, which is required for adhesion, sustained receptor signaling, and ultimately exocytosis. NK cells undergo lytic granule exocytosis in hypodense regions of a pervasive actin network. Although these requirements have been well demonstrated, neither the dynamic regulation of synaptic actin nor its specific function, however, has been determined at a nanoscale level. Here, live-cell super-resolution microscopy demonstrates nanoscale filamentous actin dynamism in NK cell lytic granule secretion. Following cell spreading, the overall content of the branched actin network at an immune synapse is stable over time and contains branched actin fibers and discrete actin foci. Similar actin architecture is generated in cytolytic T cells, although the timescale differs from that of NK cells. Individual filament displacement leads to stochastic clearance formation and disappearance, which are independent of lytic granule positioning. Actin dynamism is dependent upon branched network formation mediated by Arp2/3 and contractility generated by myosin IIA. Importantly, the use of small-molecule inhibitors demonstrates that actin dynamism is ultimately needed for granule secretion. Thus, we describe a requirement for nanoscale actin fiber rearrangement in generating the complex actin architecture that enables lytic granule secretion. F-actin forms a permissive network at the immune synapse of CTLs and NK cells The actin mesh of the mature IS of an NK cell is formed by Arp2/3 branching activity Nanoscale actin dynamism is required to allow degranulation Nanoscale dynamism is a new opportunity for regulation of cytotoxic function Natural killer cells eliminate target cells via the release of lytic granules into the immune synapse cleft. Degranulation occurs through size-permissive clearances within the cortical actin mesh of NK cells. This Arp2/3-mediated cytoskeleton undergoes constant nanoscale dynamism required to create clearances and achieve cytotoxic function.
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DOI：
10.1083/jcb.201201018
发表时间：
2012-06-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Babich A;Li S;O'Connor RS;Milone MC;Freedman BD;Burkhardt JK
通讯作者：
Burkhardt JK
影响因子：
20.3
作者：
Brown, Alice C. N.;Dobbie, Ian M.;Davis, Daniel M.
通讯作者：
Davis, Daniel M.
影响因子：
20.3
作者：
Bouma, Gerben;Mendoza-Naranjo, Ariadna;Thrasher, Adrian J.
通讯作者：
Thrasher, Adrian J.
影响因子：
32.4
作者：
Bunnell, SC;Kapoor, V;Samelson, LE
通讯作者：
Samelson, LE
影响因子：
9.2
作者：
Butler, Boyd;Cooper, John A.
通讯作者：
Cooper, John A.