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LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade

Activating mutations in LRRK2 kinase causes Parkinson’s disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with str...

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Autores principales: Dhekne, Herschel S, Yanatori, Izumi, Vides, Edmundo G, Sobu, Yuriko, Diez, Federico, Tonelli, Francesca, Pfeffer, Suzanne R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994366/
https://www.ncbi.nlm.nih.gov/pubmed/33727250
http://dx.doi.org/10.26508/lsa.202101050
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author Dhekne, Herschel S
Yanatori, Izumi
Vides, Edmundo G
Sobu, Yuriko
Diez, Federico
Tonelli, Francesca
Pfeffer, Suzanne R
author_facet Dhekne, Herschel S
Yanatori, Izumi
Vides, Edmundo G
Sobu, Yuriko
Diez, Federico
Tonelli, Francesca
Pfeffer, Suzanne R
author_sort Dhekne, Herschel S
collection PubMed
description Activating mutations in LRRK2 kinase causes Parkinson’s disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 and MyoVa relocalize to the peri-centriolar region in a phosphoRab10-dependent manner. PhosphoRab10 retains Myosin Va over pericentriolar membranes as determined by fluorescence loss in photobleaching microscopy. Without pathogenic LRRK2, RILPL2 is not essential for ciliogenesis but RILPL2 over-expression blocks ciliogenesis in RPE cells independent of tau tubulin kinase recruitment to the mother centriole. These experiments show that LRRK2 generated-phosphoRab10 dramatically redistributes a significant fraction of Myosin Va and RILPL2 to the mother centriole in a manner that likely interferes with Myosin Va’s role in ciliogenesis.
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spelling pubmed-79943662021-04-01 LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade Dhekne, Herschel S Yanatori, Izumi Vides, Edmundo G Sobu, Yuriko Diez, Federico Tonelli, Francesca Pfeffer, Suzanne R Life Sci Alliance Research Articles Activating mutations in LRRK2 kinase causes Parkinson’s disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 and MyoVa relocalize to the peri-centriolar region in a phosphoRab10-dependent manner. PhosphoRab10 retains Myosin Va over pericentriolar membranes as determined by fluorescence loss in photobleaching microscopy. Without pathogenic LRRK2, RILPL2 is not essential for ciliogenesis but RILPL2 over-expression blocks ciliogenesis in RPE cells independent of tau tubulin kinase recruitment to the mother centriole. These experiments show that LRRK2 generated-phosphoRab10 dramatically redistributes a significant fraction of Myosin Va and RILPL2 to the mother centriole in a manner that likely interferes with Myosin Va’s role in ciliogenesis. Life Science Alliance LLC 2021-03-16 /pmc/articles/PMC7994366/ /pubmed/33727250 http://dx.doi.org/10.26508/lsa.202101050 Text en © 2021 Dhekne et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Dhekne, Herschel S
Yanatori, Izumi
Vides, Edmundo G
Sobu, Yuriko
Diez, Federico
Tonelli, Francesca
Pfeffer, Suzanne R
LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade
title LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade
title_full LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade
title_fullStr LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade
title_full_unstemmed LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade
title_short LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade
title_sort lrrk2-phosphorylated rab10 sequesters myosin va with rilpl2 during ciliogenesis blockade
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994366/
https://www.ncbi.nlm.nih.gov/pubmed/33727250
http://dx.doi.org/10.26508/lsa.202101050
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