Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis

Martin Steger, Federico Diez, Herschel S. Dhekne, Pawel Lis, Raja S. Nirujogi, Ozge Karayel, Francesca Tonelli, Terina N. Martinez, Esben Lorentzen, Suzanne R. Pfeffer, Dario R. Alessi (Lead / Corresponding author), Matthias Mann

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Abstract

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, Tonelli 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.
Original languageEnglish
Article numbere31012
Pages (from-to)1-22
Number of pages22
JournaleLife
Volume6
DOIs
Publication statusPublished - 10 Nov 2017

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    Steger, M., Diez, F., Dhekne, H. S., Lis, P., Nirujogi, R. S., Karayel, O., Tonelli, F., Martinez, T. N., Lorentzen, E., Pfeffer, S. R., Alessi, D. R., & Mann, M. (2017). Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. eLife, 6, 1-22. [e31012]. https://doi.org/10.7554/eLife.31012