Natural killer (NK) cell–mediated killing involves the membrane fusion of preformed lytic granules. While the roles of actin and microtubules are well accepted during this process, the function of septins, another cytoskeletal component that associates with actin and microtubules, has not been investigated. Here we show that genetic depletion or pharmacologic stabilization of the septin cytoskeleton significantly inhibited NK cell cytotoxicity. Although the stabilization of septin filaments impaired conjugate formation, depletion of septin proteins had no impact on conjugate formation, lytic granule convergence, or MTOC polarization to the cytotoxic synapse (CS). Interestingly, septins copurify and accumulate near the polarized lytic granules at the CS, where they regulate lytic granule release. Mechanistically, we find that septin 7 interacts with the SNARE protein syntaxin 11 and facilitates its interaction with syntaxin binding protein 2 to promote lytic granule fusion. Altogether, our data identify a critical role for septins in regulating the release of lytic granule contents during NK cell–mediated killing.

中文翻译：

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septin 细胞骨架调节自然杀伤细胞裂解颗粒的释放

自然杀伤 (NK) 细胞介导的杀伤涉及预先形成的裂解颗粒的膜融合。虽然肌动蛋白和微管在此过程中的作用已被广泛接受，但脓蛋白（另一种与肌动蛋白和微管相关的细胞骨架成分）的功能尚未得到研究。在这里，我们表明，septin 细胞骨架的遗传缺失或药理学稳定显着抑制 NK 细胞的细胞毒性。尽管septin丝的稳定会损害缀合物的形成，但septin蛋白的消耗对缀合物的形成、溶解颗粒的聚集或细胞毒性突触（CS）的MTOC极化没有影响。有趣的是，脓毒症在 CS 的极化溶解颗粒附近共纯化和积累，在那里它们调节溶解颗粒的释放。从机制上讲，我们发现 septin 7 与 SNARE 蛋白突触蛋白 11 相互作用，并促进其与突触蛋白结合蛋白 2 相互作用，从而促进裂解颗粒融合。总而言之，我们的数据确定了脓毒蛋白在 NK 细胞介导的杀伤过程中调节溶解颗粒内容物释放中的关键作用。