Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling.
Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling.
复制标题
Rab5和Appl1将OCRL和INPP5B募集到吞噬体中，消耗了磷酸肌醇，并减轻AKT信号传导。
DOI：
10.1091/mbc.e11-06-0489
复制
发表时间：
2012-01
影响因子：
3.3
通讯作者：
Grinstein S
中科院分区：
文献类型：
--
作者：
Bohdanowicz M;Balkin DM;De Camilli P;Grinstein S
两个肌醇5-磷酸酶，OCRL和Inpp 5 B，成为与新生的吞噬体。这两种磷酸酶都与APPL 1衔接，APPL 1被活性Rab 5募集到吞噬体中。磷酸酶完成PI（4，5）P2和PI（3，4，5）P3的消除，促进吞噬体闭合和Akt活化的终止。吞噬体的封闭伴随着磷脂酰肌醇（4，5）-二磷酸（PtdIns（4，5）P2）从其细胞质小叶的消失。吞噬体形成过程中肌动蛋白重塑所需的PtdIns（4，5）P2的消除归因于磷脂酶C的水解和磷脂酰肌醇3-激酶的磷酸化。我们发现，两个肌醇5-磷酸酶，OCRL和Inpp 5 B，成为与新生的吞噬体。这两种磷酸酶都是Rab 5效应子，与衔接蛋白APPL 1相关，APPL 1被活性Rab 5募集到吞噬体。APPL 1的敲除或Rab 5的抑制损害了OCRL和Inpp 5 B与吞噬体的结合，并破坏了PtdIns（4，5）P2和肌动蛋白在其膜上的存在。尽管APPL 1可以作为Akt的锚，但它的缺失可能通过增加可用于产生磷脂酰肌醇（3，4，5）-三磷酸的PtdIns（4，5）P2的量来加重激酶的活化。因此，肌醇5-磷酸酶是磷酸肌醇重塑和信号传导的重要贡献者，而磷酸肌醇重塑和信号传导对于吞噬作用至关重要。
Two inositol 5-phosphatases, OCRL and Inpp5B, become associated with nascent phagosomes. Both phosphatases associate with the adaptor APPL1, which is recruited to phagosomes by active Rab5. The phosphatases complete the elimination of PI(4,5)P2 and PI(3,4,5)P3, facilitating phagosome closure and termination of Akt activation. Sealing of phagosomes is accompanied by the disappearance of phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) from their cytoplasmic leaflet. Elimination of PtdIns(4,5)P2, which is required for actin remodeling during phagosome formation, has been attributed to hydrolysis by phospholipase C and phosphorylation by phosphatidylinositol 3-kinase. We found that two inositol 5-phosphatases, OCRL and Inpp5B, become associated with nascent phagosomes. Both phosphatases, which are Rab5 effectors, associate with the adaptor protein APPL1, which is recruited to the phagosomes by active Rab5. Knockdown of APPL1 or inhibition of Rab5 impairs association of OCRL and Inpp5B with phagosomes and prolongs the presence of PtdIns(4,5)P2 and actin on their membranes. Even though APPL1 can serve as an anchor for Akt, its depletion accentuated the activation of the kinase, likely by increasing the amount of PtdIns(4,5)P2 available to generate phosphatidylinositol (3,4,5)-trisphosphate. Thus, inositol 5-phosphatases are important contributors to the phosphoinositide remodeling and signaling that are pivotal for phagocytosis.