The LRRK2 signaling network converges on a centriolar phospho-Rab10/RILPL1 complex to cause deficits in centrosome cohesion and cell polarization
Antonio Jesús Lara Ordóñez,
Rachel Fasiczka,
Belén Fernández,
Yahaira Naaldijk,
Elena Fdez,
Marian Blanca Ramírez,
Sébastien Phan,
Daniela Boassa,
Sabine Hilfiker
Affiliations
Antonio Jesús Lara Ordóñez
Department of Molecular Biology, Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, Spain
Rachel Fasiczka
Department of Anesthesiology and Department of Physiology, Pharmacology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
Belén Fernández
Department of Molecular Biology, Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, Spain
Yahaira Naaldijk
Department of Anesthesiology and Department of Physiology, Pharmacology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
Elena Fdez
Department of Molecular Biology, Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, Spain
Marian Blanca Ramírez
Department of Molecular Biology, Institute of Parasitology and Biomedicine “López-Neyra”, Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, Spain
Sébastien Phan
Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA 92093, USA
Daniela Boassa
Department of Neurosciences and National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA 92093, USA
Sabine Hilfiker
Department of Anesthesiology and Department of Physiology, Pharmacology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
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.
