RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes

Xingjian Li, Hanwen Zhu, Bik Tzu Huang, Xianting Li, Heesoo Kim, Haiyan Tan, Yuanxi Zhang, Insup Choi, Junmin Peng, Pingyi Xu, Ji Sun and Zhenyu Yue ()
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Xingjian Li: Icahn School of Medicine at Mount Sinai
Hanwen Zhu: St. Jude Children’s Research Hospital
Bik Tzu Huang: Icahn School of Medicine at Mount Sinai
Xianting Li: Icahn School of Medicine at Mount Sinai
Heesoo Kim: Icahn School of Medicine at Mount Sinai
Haiyan Tan: St. Jude Children’s Research Hospital
Yuanxi Zhang: Icahn School of Medicine at Mount Sinai
Insup Choi: Icahn School of Medicine at Mount Sinai
Junmin Peng: St. Jude Children’s Research Hospital
Pingyi Xu: The First Affiliated Hospital of Guangzhou Medical University
Ji Sun: St. Jude Children’s Research Hospital
Zhenyu Yue: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and their phosphorylation levels are elevated by Parkinson’s disease (PD)-linked mutations of LRRK2. However, the precise function of the LRRK2-regulated RAB GTPase in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brain through phosphoproteomics profiling and solve the structure of RAB12-LRRK2 protein complex through Cryo-EM analysis. Mechanistically, RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes through enhancing the phosphorylation of RAB10 and recruiting RILPL1, while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 activity. Furthermore, the ciliary and centrosome defects caused by the PD-linked LRRK2-G2019S mutation are prevented by Rab12 deletion in astrocytes. Thus, our study reveals a physiological function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis. The RAB12-LRRK2 structure offers a guidance in the therapeutic development of PD by targeting the RAB12-LRRK2 interaction.

Date: 2024
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DOI: 10.1038/s41467-024-52723-6

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