Regulation of FcγR-stimulated phagocytosis by the 72-kDa inositol polyphosphate 5-phosphatase:: SHIP1, but not the 72-kDa 5-phosphatase, regulates complement receptor 3-mediated phagocytosis by differential recruitment of these 5-phosphatases to the phagocytic cup
Regulation of FcγR-stimulated phagocytosis by the 72-kDa inositol polyphosphate 5-phosphatase:: SHIP1, but not the 72-kDa 5-phosphatase, regulates complement receptor 3-mediated phagocytosis by differential recruitment of these 5-phosphatases to the phagocytic cup
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DOI：
10.1182/blood-2007-02-073874
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发表时间：
2007-12-15
期刊：
影响因子：
20.3
通讯作者：
Mitchell, Christina A.
中科院分区：
文献类型：
--
作者：
Horan, Kristy A.;Watanabe, Ken-ichi;Mitchell, Christina A.
巨噬细胞吞噬颗粒以解决感染并清除凋亡细胞。磷酸肌醇 3-激酶生成磷脂酰肌醇-3,4,5-三磷酸 [PtdIns(3,4,5)P-3] 被限制在吞噬杯中，促进吞噬作用。含有肌醇 5-磷酸酶 1 (SHIP1) 的 PtdIns(3,4,5)P-3 5-磷酸酶 (5-ptase) Src 同源 2 (SH2) 结构域可抑制吞噬作用。我们在这里报告，另一种 PtdIns(3,4,5)P-3-5-ptase，72-kDa-5-磷酸酶 (72-5ptase)，抑制 Fc gamma 受体 (Fc gamma R)，但不抑制补体受体 3 (CR3) 介导的吞噬作用，影响伪足延伸和吞噬体闭合。相反，SHIP1 抑制 Fc gamma R 和 CR3 吞噬作用，对 CR3 刺激的吞噬作用具有更大的影响。 72-5ptase 和 SHIP1 均被动态招募至 Fc gamma R 刺激的吞噬杯，但仅 SHIP1 被招募至 CR3 刺激的吞噬杯。为了确定特定刺激后 5-ptase 是否在吞噬杯处局部降解 PtdIns(3,4,5)P-3，对特定生物传感器进行了延时成像。显性失活 72-5ptase 或 72-5ptase 小干扰 RNA (siRNA) 的转染导致吞噬杯处响应 Fc-yR 而非 CR3 刺激的 PtdIns(3,4,5)P-3 扩增和延长。相比之下，来自 Ship1(-/-)/AktPH-GFP 转基因小鼠的巨噬细胞响应 CR3 激活，在杯中表现出增加和持续的 PtdIns(3,4,5)P-3，而 Fc gamma R 激活变化最小。因此，72-5ptase 和 SHIP1 通过控制吞噬杯处 PtdIns(3,4,5)P-3 的幅度和持续时间，在调节 Fc-yR 与 CR3 刺激的吞噬作用方面表现出特异性。
Macrophages phagocytose particles to resolve infections and remove apoptotic cells. Phosphoinositide 3-kinase generates phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P-3] is restricted to the phagocytic cup, promoting phagocytosis. The PtdIns(3,4,5)P-3 5-phosphatase (5-ptase) Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1) inhibits phagocytosis. We report here that another PtdIns(3,4,5)P-3-5-ptase, the 72-kDa-5-phosphatase (72-5ptase), inhibits Fc gamma receptor (Fc gamma R)- but not complement receptor 3 (CR3)-mediated phagocytosis, affecting pseudopod extension and phagosome closure. In contrast, SHIP1 inhibited Fc gamma R and CR3 phagocytosis with greater effects on CR3-stimulated phagocytosis. The 72-5ptase and SHIP1 were both dynamically recruited to Fc gamma R-stimulated phagocytic cups, but only SHIP1 was recruited to CR3-stimulated phagocytic cups. To determine whether 5-ptases focally degrade PtdIns(3,4,5)P-3 at the phagocytic cup after specific stimuli, time-lapse imaging of specific biosensors was performed. Transfection of dominant-negative 72-5ptase or 72-5ptase small interfering RNA (siRNA) resulted in amplified and prolonged PtdIns(3,4,5)P-3 at the phagocytic cup in response to Fc-yR- but not CR3-stimulation. In contrast, macrophages from Ship1(-/-)/AktPH-GFP transgenic mice exhibited increased and sustained PtdIns(3,4,5)P-3 at the cup in response to CR3 activation, with minimal changes to Fc gamma R activation. Therefore, 72-5ptase and SHIP1 exhibit specificity in regulating Fc-yR- versus CR3-stimulated phagocytosis by controlling the amplitude and duration of PtdIns(3,4,5)P-3 at the phagocytic cup.