Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins.
Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins.
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DOI：
10.1038/ncomms9623
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发表时间：
2015-10-14
影响因子：
16.6
通讯作者：
Grinstein S
中科院分区：
文献类型：
--
作者：
Schlam D;Bagshaw RD;Freeman SA;Collins RF;Pawson T;Fairn GD;Grinstein S
吞噬作用负责消除大小不一的颗粒，从大型真菌或衰弱的细胞到小型细菌。尽管表面上相似，但涉及的分子机制不同：吞噬大目标需要磷脂酰肌醇3-激酶(PI3K)，而小目标不需要。在这里，我们报告了RAC和CDC42在吞噬杯中的失活对于完成大颗粒的内化是必不可少的。通过对62个RhoGAP家族成员的筛选，我们证明了ARHGAP12、ARHGAP25和SH3BP1负责GTP酶的失活。使这些RhoGAP沉默会损害大目标的吞噬功能。通过PI3K的产物，间隙被招募到大的-但不是小的-吞噬杯中，在那里它们协同灭活RAC和CDC42。值得注意的是，在吞噬小目标的过程中，大噬菌体形成过程中磷脂酰肌醇3，4，5-三磷酸的显著积累特征并不明显，这是由于不同大小的颗粒吞噬过程中RhoGAP分布的反差和对PI3K的不同要求。吞噬大颗粒(但不是小颗粒)需要PI 3-激酶活性。在这里，施拉姆等人。结果表明，Rho GTP酶激活蛋白通过PI 3-K的产物募集到吞噬杯中，导致RAC和CDC42的局部失活，并允许大颗粒的内化完成。
Phagocytosis is responsible for the elimination of particles of widely disparate sizes, from large fungi or effete cells to small bacteria. Though superficially similar, the molecular mechanisms involved differ: engulfment of large targets requires phosphoinositide 3-kinase (PI3K), while that of small ones does not. Here, we report that inactivation of Rac and Cdc42 at phagocytic cups is essential to complete internalization of large particles. Through a screen of 62 RhoGAP-family members, we demonstrate that ARHGAP12, ARHGAP25 and SH3BP1 are responsible for GTPase inactivation. Silencing these RhoGAPs impairs phagocytosis of large targets. The GAPs are recruited to large—but not small—phagocytic cups by products of PI3K, where they synergistically inactivate Rac and Cdc42. Remarkably, the prominent accumulation of phosphatidylinositol 3,4,5-trisphosphate characteristic of large-phagosome formation is less evident during phagocytosis of small targets, accounting for the contrasting RhoGAP distribution and the differential requirement for PI3K during phagocytosis of dissimilarly sized particles. Phagocytosis of large (but not small) particles requires PI 3-kinase activity. Here, Schlam et al. show that Rho GTPase-activating proteins are recruited to the phagocytic cup by products of PI 3-kinase, resulting in the local inactivation of Rac and Cdc42 and allowing for the completion of internalization of large particles.