Cargando…

Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis

PPM1H phosphatase reverses Parkinson’s disease-associated, Leucine Rich Repeat Kinase 2-mediated Rab GTPase phosphorylation. We show here that PPM1H relies on an N-terminal amphipathic helix for Golgi localization. The amphipathic helix enables PPM1H to bind to liposomes in vitro, and small, highly...

Descripción completa

Detalles Bibliográficos
Autores principales: Yeshaw, Wondwossen M., Adhikari, Ayan, Chiang, Claire Y., Dhekne, Herschel S., Wawro, Paulina S., Pfeffer, Suzanne R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10622911/
https://www.ncbi.nlm.nih.gov/pubmed/37889931
http://dx.doi.org/10.1073/pnas.2315171120
_version_ 1785130643405930496
author Yeshaw, Wondwossen M.
Adhikari, Ayan
Chiang, Claire Y.
Dhekne, Herschel S.
Wawro, Paulina S.
Pfeffer, Suzanne R.
author_facet Yeshaw, Wondwossen M.
Adhikari, Ayan
Chiang, Claire Y.
Dhekne, Herschel S.
Wawro, Paulina S.
Pfeffer, Suzanne R.
author_sort Yeshaw, Wondwossen M.
collection PubMed
description PPM1H phosphatase reverses Parkinson’s disease-associated, Leucine Rich Repeat Kinase 2-mediated Rab GTPase phosphorylation. We show here that PPM1H relies on an N-terminal amphipathic helix for Golgi localization. The amphipathic helix enables PPM1H to bind to liposomes in vitro, and small, highly curved liposomes stimulate PPM1H activity. We artificially anchored PPM1H to the Golgi, mitochondria, or mother centriole. Our data show that regulation of Rab10 GTPase phosphorylation requires PPM1H access to Rab10 at or near the mother centriole. Moreover, poor colocalization of Rab12 explains in part why it is a poor substrate for PPM1H in cells but not in vitro. These data support a model in which localization drives PPM1H substrate selection and centriolar PPM1H is critical for regulation of Rab GTPase-regulated ciliogenesis. Moreover, Golgi localized PPM1H may maintain active Rab GTPases on the Golgi to carry out their nonciliogenesis-related functions in membrane trafficking.
format Online
Article
Text
id pubmed-10622911
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-106229112023-11-04 Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis Yeshaw, Wondwossen M. Adhikari, Ayan Chiang, Claire Y. Dhekne, Herschel S. Wawro, Paulina S. Pfeffer, Suzanne R. Proc Natl Acad Sci U S A Biological Sciences PPM1H phosphatase reverses Parkinson’s disease-associated, Leucine Rich Repeat Kinase 2-mediated Rab GTPase phosphorylation. We show here that PPM1H relies on an N-terminal amphipathic helix for Golgi localization. The amphipathic helix enables PPM1H to bind to liposomes in vitro, and small, highly curved liposomes stimulate PPM1H activity. We artificially anchored PPM1H to the Golgi, mitochondria, or mother centriole. Our data show that regulation of Rab10 GTPase phosphorylation requires PPM1H access to Rab10 at or near the mother centriole. Moreover, poor colocalization of Rab12 explains in part why it is a poor substrate for PPM1H in cells but not in vitro. These data support a model in which localization drives PPM1H substrate selection and centriolar PPM1H is critical for regulation of Rab GTPase-regulated ciliogenesis. Moreover, Golgi localized PPM1H may maintain active Rab GTPases on the Golgi to carry out their nonciliogenesis-related functions in membrane trafficking. National Academy of Sciences 2023-10-27 2023-10-31 /pmc/articles/PMC10622911/ /pubmed/37889931 http://dx.doi.org/10.1073/pnas.2315171120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Yeshaw, Wondwossen M.
Adhikari, Ayan
Chiang, Claire Y.
Dhekne, Herschel S.
Wawro, Paulina S.
Pfeffer, Suzanne R.
Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis
title Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis
title_full Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis
title_fullStr Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis
title_full_unstemmed Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis
title_short Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis
title_sort localization of ppm1h phosphatase tunes parkinson’s disease-linked lrrk2 kinase-mediated rab gtpase phosphorylation and ciliogenesis
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10622911/
https://www.ncbi.nlm.nih.gov/pubmed/37889931
http://dx.doi.org/10.1073/pnas.2315171120
work_keys_str_mv AT yeshawwondwossenm localizationofppm1hphosphatasetunesparkinsonsdiseaselinkedlrrk2kinasemediatedrabgtpasephosphorylationandciliogenesis
AT adhikariayan localizationofppm1hphosphatasetunesparkinsonsdiseaselinkedlrrk2kinasemediatedrabgtpasephosphorylationandciliogenesis
AT chiangclairey localizationofppm1hphosphatasetunesparkinsonsdiseaselinkedlrrk2kinasemediatedrabgtpasephosphorylationandciliogenesis
AT dhekneherschels localizationofppm1hphosphatasetunesparkinsonsdiseaselinkedlrrk2kinasemediatedrabgtpasephosphorylationandciliogenesis
AT wawropaulinas localizationofppm1hphosphatasetunesparkinsonsdiseaselinkedlrrk2kinasemediatedrabgtpasephosphorylationandciliogenesis
AT pfeffersuzanner localizationofppm1hphosphatasetunesparkinsonsdiseaselinkedlrrk2kinasemediatedrabgtpasephosphorylationandciliogenesis