Role of Integrins in Natural Killer Cell Function

在NK细胞中，与ICAM家族成员结合的β2整合素不仅足以促进与靶细胞的黏附，而且还能促进细胞内裂解颗粒向靶细胞的极化。通过对经β2整合素LFA-1刺激的NK细胞进行无偏质量谱和生物信息学分析，发现了一条控制颗粒向靶细胞极化的完整信号通路。除了测试了11种蛋白质在颗粒极化中的作用外，还有12种孤儿蛋白质没有已知的相互作用。在质谱学分析中得分最高的孤儿蛋白是细胞粘附素4。细胞粘附素家族的4个成员携带一个针对小GTP酶Arf家族成员的具有鸟嘌呤交换因子活性的PH结构域和Sec7结构域。虽然细胞粘素1在β2整合素LFA-1的内向外信号转导中起作用，但细胞粘素4的功能尚不清楚。细胞粘蛋白4的沉默而不是细胞粘蛋白1的沉默导致了颗粒极化的缺陷。据我们所知，这是第一次将功能归因于细胞粘附素4。

In NK cells, beta2 integrin binding to ICAM family members is sufficient to promote not only adhesion to target cells, but also the polarization of intracellular lytic granules towards the target. Using unbiased mass spectrometry and bioinformatics analysis of NK cells that had been stimulated through beta2 integrin LFA-1 resulted in the discovery of a complete signaling pathway that controls granule polarization toward the target cell. In addition to a network of 11 proteins tested for a role in granule polarization, there were 12 orphan proteins with no known interactions. The orphan protein with the highest score in the mass spectrometry analysis was cytohesin 4. The four members of the cytohesin family carry a PH domain and a Sec7 domain with guanine exchange factor activity for members of the small GTPase Arf family. While cytohesin 1 plays a role in inside-out signaling for beta2 integrin LFA-1, the function of cytohesin 4 is unknown. Silencing of cytohesin 4 but not cytohesin 1 resulted in defective granule polarization. To our knowledge, this is the first time a function has been attributed to cytohesin 4.