Genetic variation in LRRK2 associates with the susceptibility to Parkinson's disease, Crohn's disease, and mycobacteria infection. High expression of LRRK2 and its substrate Rab10 occurs in phagocytic cells in the immune system. In mouse and human primary macrophages, dendritic cells, and microglia‐like cells, we find that Rab10 specifically regulates a specialized form of endocytosis known as macropinocytosis, without affecting phagocytosis or clathrin‐mediated endocytosis. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3‐positive GTP‐Rab10, before EEA1 and Rab5 recruitment to early macropinosomes occurs. Macropinosome cargo in macrophages includes CCR5, CD11b, and MHCII, and LRRK2‐phosphorylation of Rab10 potently blocks EHBP1L1‐mediated recycling tubules and cargo turnover. EHBP1L1 overexpression competitively inhibits LRRK2‐phosphorylation of Rab10, mimicking the effects of LRRK2 kinase inhibition in promoting cargo recycling. Both Rab10 knockdown and LRRK2 kinase inhibition potently suppress the maturation of macropinosome‐derived CCR5‐loaded signaling endosomes that are critical for CCL5‐induced immunological responses that include Akt activation and chemotaxis. These data support a novel signaling axis in the endolysosomal system whereby LRRK2‐mediated Rab10 phosphorylation stalls vesicle fast recycling to promote PI3K‐Akt immunological responses.

中文翻译：

---

LRRK2 和 Rab10 协调巨胞饮作用以介导吞噬细胞的免疫反应。

LRRK2 的遗传变异与帕金森病、克罗恩病和分枝杆菌感染的易感性相关。LRRK2 及其底物 Rab10 在免疫系统的吞噬细胞中高表达。在小鼠和人类原代巨噬细胞、树突状细胞和小胶质细胞样细胞中，我们发现 Rab10 特异性调节一种特殊形式的内吞作用，称为巨胞饮作用，而不影响吞噬作用或网格蛋白介导的内吞作用。在 EEA1 和 Rab5 募集到早期巨脂质体之前，LRRK2 磷酸化细胞质 PI(3,4,5)P3 阳性 GTP-Rab10。巨噬细胞中的巨噬细胞货物包括 CCR5、CD11b 和 MHCII，Rab10 的 LRRK2 磷酸化可有效阻断 EHBP1L1 介导的回收小管和货物周转。EHBP1L1 过表达竞争性抑制 Rab10 的 LRRK2 磷酸化，模仿 LRRK2 激酶抑制在促进货物循环中的作用。Rab10 敲低和 LRRK2 激酶抑制均可有效抑制巨胞质体衍生的 CCR5 负载信号内体的成熟，这些信号内体对于 CCL5 诱导的免疫反应（包括 Akt 激活和趋化性）至关重要。这些数据支持内溶酶体系统中的一个新的信号轴，LRRK2 介导的 Rab10 磷酸化可阻止囊泡快速回收，从而促进 PI3K-Akt 免疫反应。