PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins

Kerryn Berndsen, Paweł Lis, Wondwossen M. Yeshaw, Paulina S. Wawro, Raja Nirujogi, Melanie Wightman, Thomas Macartney, Mark Dorward, Axel Knebel, Francesca Tonelli, Suzanne R. Pfeffer, Dario Alessi (Lead / Corresponding author)

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Abstract

Mutations that activate LRRK2 protein kinase cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all human protein phosphatases revealed that a poorly studied protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins. PPM1H knockout increased endogenous Rab phosphorylation and inhibited Rab dephosphorylation in human A549 cells. Overexpression of PPM1H suppressed LRRK2-mediated Rab phosphorylation. PPM1H also efficiently and directly dephosphorylated Rab8A in biochemical studies. A "substrate-trapping" PPM1H mutant (Asp288Ala) binds with high affinity to endogenous, LRRK2-phosphorylated Rab proteins, thereby blocking dephosphorylation seen upon addition of LRRK2 inhibitors. PPM1H is localized to the Golgi and its knockdown suppresses primary cilia formation, similar to pathogenic LRRK2. Thus, PPM1H acts as a key modulator of LRRK2 signaling by controlling dephosphorylation of Rab proteins. PPM1H activity enhancers could offer a new therapeutic approach to prevent or treat Parkinson's disease.

Original languageEnglish
Article numbere50416
Pages (from-to)1-37
Number of pages37
JournaleLife
Volume8
Early online date30 Oct 2019
DOIs
Publication statusPublished - 12 Nov 2019

Fingerprint

Phosphoric Monoester Hydrolases
Phosphorylation
Phosphoprotein Phosphatases
Parkinson Disease
rab GTP-Binding Proteins
Proteins
Cilia
Protein Kinases
Modulators
Small Interfering RNA
Switches
Mutation
Substrates
Therapeutics

Keywords

  • LRRK2
  • Parkinson's disease
  • Rab GTPase
  • biochemistry
  • cell signalling
  • chemical biology
  • human
  • mouse
  • protein kinase
  • protein phosphatase

Cite this

Berndsen, Kerryn ; Lis, Paweł ; Yeshaw, Wondwossen M. ; Wawro, Paulina S. ; Nirujogi, Raja ; Wightman, Melanie ; Macartney, Thomas ; Dorward, Mark ; Knebel, Axel ; Tonelli, Francesca ; Pfeffer, Suzanne R. ; Alessi, Dario. / PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins. In: eLife. 2019 ; Vol. 8. pp. 1-37.
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abstract = "Mutations that activate LRRK2 protein kinase cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all human protein phosphatases revealed that a poorly studied protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins. PPM1H knockout increased endogenous Rab phosphorylation and inhibited Rab dephosphorylation in human A549 cells. Overexpression of PPM1H suppressed LRRK2-mediated Rab phosphorylation. PPM1H also efficiently and directly dephosphorylated Rab8A in biochemical studies. A {"}substrate-trapping{"} PPM1H mutant (Asp288Ala) binds with high affinity to endogenous, LRRK2-phosphorylated Rab proteins, thereby blocking dephosphorylation seen upon addition of LRRK2 inhibitors. PPM1H is localized to the Golgi and its knockdown suppresses primary cilia formation, similar to pathogenic LRRK2. Thus, PPM1H acts as a key modulator of LRRK2 signaling by controlling dephosphorylation of Rab proteins. PPM1H activity enhancers could offer a new therapeutic approach to prevent or treat Parkinson's disease.",
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PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins. / Berndsen, Kerryn; Lis, Paweł; Yeshaw, Wondwossen M.; Wawro, Paulina S.; Nirujogi, Raja; Wightman, Melanie; Macartney, Thomas; Dorward, Mark; Knebel, Axel; Tonelli, Francesca; Pfeffer, Suzanne R.; Alessi, Dario (Lead / Corresponding author).

In: eLife, Vol. 8, e50416, 12.11.2019, p. 1-37.

Research output: Contribution to journalArticle

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AU - Berndsen, Kerryn

AU - Lis, Paweł

AU - Yeshaw, Wondwossen M.

AU - Wawro, Paulina S.

AU - Nirujogi, Raja

AU - Wightman, Melanie

AU - Macartney, Thomas

AU - Dorward, Mark

AU - Knebel, Axel

AU - Tonelli, Francesca

AU - Pfeffer, Suzanne R.

AU - Alessi, Dario

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KW - cell signalling

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