Proteomics

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LRRK2-RAB12 Complex Suppresses Primary Ciliogenesis and Regulates Centrosome Homeostasis in Astrocytes

ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases and this phosphorylation is elevated by Parkinson’s disease (PD)-linked mutations of LRRK2. However, the precise function of the specific RAB GTPase targeted by LRRK2 signaling remains to be elucidated. Here we solve the structure of LRRK2-RAB12 protein complex and reveal a physiological role of RAB12 in the brain. We find that RAB12 corporates with LRRK2 to inhibits the primary ciliogenesis and regulate centrosome homeostasis in astrocytes through recruiting RILPL1 and enhancing the phosphorylation of RAB10, while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 kinase activity. Furthermore, the ciliary deficits and centrosome alteration caused by the PD-linked LRRK2-G2019S mutation are prevented by disrupting Rab12 in astrocytes. Our study identifies a central role for the LRRK2-RAB12 complex in regulating ciliogenesis and centrosome homeostasis, and the LRRK2-RAB12 structure offers guidance in therapeutic development by targeting the LRRK2-RAB12 interaction.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: Haiyan Tan  

LAB HEAD: Junmin Peng

PROVIDER: PXD048732 | Pride | 2025-01-18

REPOSITORIES: pride

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mouse_pho_01.1.pepXML Pepxml
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mouse_pho_02.1.pepXML Pepxml
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RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes.

Li Xingjian X   Zhu Hanwen H   Huang Bik Tzu BT   Li Xianting X   Kim Heesoo H   Tan Haiyan H   Zhang Yuanxi Y   Choi Insup I   Peng Junmin J   Xu Pingyi P   Sun Ji J   Yue Zhenyu Z  

Nature communications 20240929 1

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 coop  ...[more]

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