We previously reported that Parkinson’s disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12. Induction of primary cilia formation by serum starvation led to a two-fold reduction in ciliogenesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice. These results implicate LRRK2 in primary ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies.

中文翻译：

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LRRK2 介导的 Rab GTPase 磷酸化的系统蛋白质组学分析建立了与纤毛发生的联系

我们之前曾报道帕金森病 (PD) 激酶 LRRK2 磷酸化 Rab GTPases 亚群的 switch-II 结构域中的保守残基（Steger 等，2016）（PMID：26824392）。在这里，我们系统地分析了 Rab 蛋白家族，发现其中 14 个（Rab3A/B/C/D、Rab5A/B/C、Rab8A/B、Rab10、Rab12、Rab29、Rab35 和 Rab43）被 LRRK2 特异性磷酸化，有证据表明其中 10 个（Rab3A/B/C/D、Rab8A/B、Rab10、Rab12、Rab35 和 Rab43）存在内源性磷酸化。亲和富集质谱显示主要的纤毛发生调节因子 RILPL1 与 LRRK2 磷酸化形式的 Rab8A 和 Rab10 特异性相互作用，而 RILPL2 与磷酸化的 Rab8A、Rab10 和 Rab12 结合。通过血清饥饿诱导初级纤毛形成导致源自致病性 LRRK2-R1441G 敲入小鼠的成纤维细胞纤毛发生减少两倍。这些结果暗示 LRRK2 参与初级纤毛发生，并表明纤毛上 Rab 介导的蛋白质转运和/或信号传导缺陷可能导致 LRRK2 依赖性病理。