Cargando…

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

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 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, Rab...

Descripción completa

Detalles Bibliográficos
Autores principales: Steger, Martin, Diez, Federico, Dhekne, Herschel S, Lis, Pawel, Nirujogi, Raja S, Karayel, Ozge, Tonelli, Francesca, Martinez, Terina N, Lorentzen, Esben, Pfeffer, Suzanne R, Alessi, Dario R, Mann, Matthias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695910/
https://www.ncbi.nlm.nih.gov/pubmed/29125462
http://dx.doi.org/10.7554/eLife.31012
_version_ 1783280378843234304
author Steger, Martin
Diez, Federico
Dhekne, Herschel S
Lis, Pawel
Nirujogi, Raja S
Karayel, Ozge
Tonelli, Francesca
Martinez, Terina N
Lorentzen, Esben
Pfeffer, Suzanne R
Alessi, Dario R
Mann, Matthias
author_facet Steger, Martin
Diez, Federico
Dhekne, Herschel S
Lis, Pawel
Nirujogi, Raja S
Karayel, Ozge
Tonelli, Francesca
Martinez, Terina N
Lorentzen, Esben
Pfeffer, Suzanne R
Alessi, Dario R
Mann, Matthias
author_sort Steger, Martin
collection PubMed
description 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 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.
format Online
Article
Text
id pubmed-5695910
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-56959102017-11-22 Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis Steger, Martin Diez, Federico Dhekne, Herschel S Lis, Pawel Nirujogi, Raja S Karayel, Ozge Tonelli, Francesca Martinez, Terina N Lorentzen, Esben Pfeffer, Suzanne R Alessi, Dario R Mann, Matthias eLife Biochemistry and Chemical Biology 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 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. eLife Sciences Publications, Ltd 2017-11-10 /pmc/articles/PMC5695910/ /pubmed/29125462 http://dx.doi.org/10.7554/eLife.31012 Text en © 2017, Steger et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Steger, Martin
Diez, Federico
Dhekne, Herschel S
Lis, Pawel
Nirujogi, Raja S
Karayel, Ozge
Tonelli, Francesca
Martinez, Terina N
Lorentzen, Esben
Pfeffer, Suzanne R
Alessi, Dario R
Mann, Matthias
Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis
title Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis
title_full Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis
title_fullStr Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis
title_full_unstemmed Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis
title_short Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis
title_sort systematic proteomic analysis of lrrk2-mediated rab gtpase phosphorylation establishes a connection to ciliogenesis
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695910/
https://www.ncbi.nlm.nih.gov/pubmed/29125462
http://dx.doi.org/10.7554/eLife.31012
work_keys_str_mv AT stegermartin systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT diezfederico systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT dhekneherschels systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT lispawel systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT nirujogirajas systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT karayelozge systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT tonellifrancesca systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT martinezterinan systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT lorentzenesben systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT pfeffersuzanner systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT alessidarior systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis
AT mannmatthias systematicproteomicanalysisoflrrk2mediatedrabgtpasephosphorylationestablishesaconnectiontociliogenesis