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The LRRK2 signaling network converges on a centriolar phospho-Rab10/RILPL1 complex to cause deficits in centrosome cohesion and cell polarization

Lara Ordóñez, Antonio Jesús, Fasiczka, Rachel, Fernández, Belén, Naaldijk, Yahaira, Fdez, Elena, Blanca Ramírez, Marian, Phan, Sébastien, Boassa, Daniela, Hilfiker, Sabine·2022·Biology Open
DOI 10.1242/bio.059468PMC PMC9346292
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Abstract

The Parkinson's-disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases including Rab8 and Rab10, which enhances their binding to RILPL1 and RILPL2. The nascent interaction between phospho-Rab10 and RILPL1 blocks ciliogenesis in vitro and in the intact brain, and interferes with the cohesion of duplicated centrosomes in dividing cells. We show here that regulators of the LRRK2 signaling pathway including vps35 and PPM1H converge upon causing centrosomal deficits. The cohesion alterations do not require the presence of other LRRK2 kinase substrates including Rab12, Rab35 and Rab43 or the presence of RILPL2. Rather, they depend on the RILPL1-mediated centrosomal accumulation of phosphorylated Rab10. RILPL1 localizes to the subdistal appendage of the mother centriole, followed by recruitment of the LRRK2-phosphorylated Rab proteins to cause the centrosomal defects. The centrosomal alterations impair cell polarization as monitored by scratch wound assays which is reverted by LRRK2 kinase inhibition. These data reveal a common molecular pathway by which enhanced LRRK2 kinase activity impacts upon centrosome-related events to alter the normal biology of a cell.

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  • Rab10 was identified as phosphorylated by LRRK2 combining two independent genetic and chemical phosphoproteomic screens and has been validated in subsequent studies.

    “Rab10 specifically was identified as phosphorylated by LRRK2 combining two independent genetic and chemical phosphoproteomic screens and has been validated in subsequent studies [19, 28, 32, 34, 35, 41, 79].”

    From Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain (2023) · cites this paper as [34]

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Metadata

Authors
Lara Ordóñez, A. J., Fasiczka, R., Fernández, B., Naaldijk, Y., Fdez, E., Blanca Ramírez, M., Phan, S., Boassa, D., & Hilfiker, S.
Venue
Biology Open
Publisher
The Company of Biologists
Published
2022-07-29
Volume
11
Issue
8
ISSN
2046-6390
DOI
10.1242/bio.059468
PMC
PMC9346292
Cited by
28
References
6
Language
en
Licence
creativecommons.org/licenses/by/4.0 (vor)
Funders
  • Michael J. Fox Foundation for Parkinson's research
  • Spanish Ministry of Economy and Competitiveness (SAF2017-89402-R)
  • Spanish Ministry of Education, Culture and Sport (FPU15/05233)
  • Spanish Ministry of Science, Innovation and Universities (EST18/00412)
  • National Institute of Health (R01GM086197)
  • Branfman Family Foundation
  • National Center for Microscopy and Imaging Research (P41 GM103412])
  • Rutgers New Jersey Medical School

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