biostudies-literatureUnknownLi XNINDS NIH HHSLeucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and the phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the specific RAB GTPase targeted by LRRK2 signaling in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brains 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 Rab interacting lysosomal protein like 1 (RILPL1), while the functions of RAB12 require a direct interaction with LRRK2 anbioRxiv : the preprint server for biology2024.07.17.603999https://www.ebi.ac.uk/biostudies/studies/S-EPMC11275936biostudies-literatureRAB12-LRRK2 Complex Suppresses Primary Ciliogenesis and Regulates Centrosome Homeostasis in Astrocytes.PMC11275936R01 NS129795Li XHuang BTTan HXu PKim HZhang YZhu HChoi IPeng JSun JYue ZfalseRAB12-LRRK2 Complex Suppresses Primary Ciliogenesis and Regulates Centrosome Homeostasis in Astrocytes.Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and the phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the specific RAB GTPase targeted by LRRK2 signaling in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brains 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 Rab interacting lysosomal protein like 1 (RILPL1), while the functions of RAB12 require a direct interaction with LRRK2 an2024-01-01T00:00:00Z2024 Jul2026-04-07T21:19:37.221Z2025-04-04T02:58:22.243ZS-EPMC112759363907132810.1101/2024.07.17.603999