Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1.
Identifieur interne : 000541 ( Main/Exploration ); précédent : 000540; suivant : 000542Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1.
Auteurs : Yu-Chiang Lai [Royaume-Uni] ; Chandana Kondapalli [Royaume-Uni] ; Ronny Lehneck [Allemagne] ; James B. Procter [Royaume-Uni] ; Brian D. Dill [Royaume-Uni] ; Helen I. Woodroof [Royaume-Uni] ; Robert Gourlay [Royaume-Uni] ; Mark Peggie [Royaume-Uni] ; Thomas J. Macartney [Royaume-Uni] ; Olga Corti [France] ; Jean-Christophe Corvol [France] ; David G. Campbell [Royaume-Uni] ; Aymelt Itzen [Allemagne] ; Matthias Trost [Royaume-Uni] ; Miratul Mk Muqit [Royaume-Uni]Source :
- The EMBO journal [ 1460-2075 ] ; 2015.
English descriptors
- KwdEn :
- Amino Acid Substitution, Enzyme Activation (genetics), HEK293 Cells, HeLa Cells, Humans, Mutation, Missense, Oncogene Proteins (genetics), Oncogene Proteins (metabolism), Parkinsonian Disorders (genetics), Parkinsonian Disorders (metabolism), Parkinsonian Disorders (pathology), Phosphorylation (genetics), Protein Kinases (genetics), Protein Kinases (metabolism), Protein-Serine-Threonine Kinases (genetics), Protein-Serine-Threonine Kinases (metabolism), rab GTP-Binding Proteins (genetics), rab GTP-Binding Proteins (metabolism).
- MESH :
- chemical , genetics : Oncogene Proteins, Protein Kinases, Protein-Serine-Threonine Kinases, rab GTP-Binding Proteins.
- genetics : Enzyme Activation, Parkinsonian Disorders, Phosphorylation.
- chemical , metabolism : Oncogene Proteins, Parkinsonian Disorders, Protein Kinases, Protein-Serine-Threonine Kinases, rab GTP-Binding Proteins.
- pathology : Parkinsonian Disorders.
- Amino Acid Substitution, HEK293 Cells, HeLa Cells, Humans, Mutation, Missense.
- mix :
Abstract
Mutations in the PTEN-induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson's disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser(65)) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1-dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub-family of Rab GTPases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser(111)) in response to PINK1 activation. Using phospho-specific antibodies raised against Ser(111) of each of the Rabs, we demonstrate that Rab Ser(111) phosphorylation occurs specifically in response to PINK1 activation and is abolished in HeLa PINK1 knockout cells and mutant PINK1 PD patient-derived fibroblasts stimulated by mitochondrial depolarisation. We provide evidence that Rab8A GTPase Ser(111) phosphorylation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser(111) phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser(65). We further show mechanistically that phosphorylation at Ser(111) significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor (GEF), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK1 is able to regulate the phosphorylation of Rab GTPases and indicate that monitoring phosphorylation of Rab8A/8B/13 at Ser(111) may represent novel biomarkers of PINK1 activity in vivo. Our findings also suggest that disruption of Rab GTPase-mediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson's disease.
Url:
DOI: 10.15252/embj.201591593
PubMed: 26471730
Affiliations:
- Allemagne, France, Royaume-Uni
- Bavière, District de Haute-Bavière, Île-de-France
- Munich, Paris
- Université Louis-et-Maximilien de Munich
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Le document en format XML
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<affiliation wicri:level="4"><nlm:affiliation>Centre for Integrated Protein Science Munich, Department Chemistry Technische Universität München, Garching, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Centre for Integrated Protein Science Munich, Department Chemistry Technische Universität München, Garching</wicri:regionArea>
<wicri:noRegion>Garching</wicri:noRegion>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
<placeName><settlement type="city">Munich</settlement>
<region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Trost, Matthias" sort="Trost, Matthias" uniqKey="Trost M" first="Matthias" last="Trost">Matthias Trost</name>
<affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK m.trost@dundee.ac.uk m.muqit@dundee.ac.uk.</nlm:affiliation>
<country wicri:rule="url">Royaume-Uni</country>
<wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea>
<wicri:noRegion>Dundee</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Muqit, Miratul Mk" sort="Muqit, Miratul Mk" uniqKey="Muqit M" first="Miratul Mk" last="Muqit">Miratul Mk Muqit</name>
<affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK College of Medicine, Dentistry & Nursing, University of Dundee, Dundee, UK m.trost@dundee.ac.uk m.muqit@dundee.ac.uk.</nlm:affiliation>
<country wicri:rule="url">Royaume-Uni</country>
<wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK College of Medicine, Dentistry & Nursing, University of Dundee, Dundee</wicri:regionArea>
<wicri:noRegion>Dundee</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">The EMBO journal</title>
<idno type="eISSN">1460-2075</idno>
<imprint><date when="2015" type="published">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Substitution</term>
<term>Enzyme Activation (genetics)</term>
<term>HEK293 Cells</term>
<term>HeLa Cells</term>
<term>Humans</term>
<term>Mutation, Missense</term>
<term>Oncogene Proteins (genetics)</term>
<term>Oncogene Proteins (metabolism)</term>
<term>Parkinsonian Disorders (genetics)</term>
<term>Parkinsonian Disorders (metabolism)</term>
<term>Parkinsonian Disorders (pathology)</term>
<term>Phosphorylation (genetics)</term>
<term>Protein Kinases (genetics)</term>
<term>Protein Kinases (metabolism)</term>
<term>Protein-Serine-Threonine Kinases (genetics)</term>
<term>Protein-Serine-Threonine Kinases (metabolism)</term>
<term>rab GTP-Binding Proteins (genetics)</term>
<term>rab GTP-Binding Proteins (metabolism)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Oncogene Proteins</term>
<term>Protein Kinases</term>
<term>Protein-Serine-Threonine Kinases</term>
<term>rab GTP-Binding Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Enzyme Activation</term>
<term>Parkinsonian Disorders</term>
<term>Phosphorylation</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Oncogene Proteins</term>
<term>Parkinsonian Disorders</term>
<term>Protein Kinases</term>
<term>Protein-Serine-Threonine Kinases</term>
<term>rab GTP-Binding Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Parkinsonian Disorders</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term>
<term>HEK293 Cells</term>
<term>HeLa Cells</term>
<term>Humans</term>
<term>Mutation, Missense</term>
</keywords>
<keywords scheme="mix" xml:lang="en"><term> Proteolysis & Proteomics</term>
<term>Methods & Resources</term>
<term>PINK1</term>
<term>Parkinson's disease</term>
<term>Post-translational Modifications</term>
<term>Rab GTPases Subject Categories Membrane & Intracellular Transport</term>
<term>phosphoproteomics</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Mutations in the PTEN-induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson's disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser(65)) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1-dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub-family of Rab GTPases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser(111)) in response to PINK1 activation. Using phospho-specific antibodies raised against Ser(111) of each of the Rabs, we demonstrate that Rab Ser(111) phosphorylation occurs specifically in response to PINK1 activation and is abolished in HeLa PINK1 knockout cells and mutant PINK1 PD patient-derived fibroblasts stimulated by mitochondrial depolarisation. We provide evidence that Rab8A GTPase Ser(111) phosphorylation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser(111) phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser(65). We further show mechanistically that phosphorylation at Ser(111) significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor (GEF), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK1 is able to regulate the phosphorylation of Rab GTPases and indicate that monitoring phosphorylation of Rab8A/8B/13 at Ser(111) may represent novel biomarkers of PINK1 activity in vivo. Our findings also suggest that disruption of Rab GTPase-mediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson's disease.</div>
</front>
</TEI>
<affiliations><list><country><li>Allemagne</li>
<li>France</li>
<li>Royaume-Uni</li>
</country>
<region><li>Bavière</li>
<li>District de Haute-Bavière</li>
<li>Île-de-France</li>
</region>
<settlement><li>Munich</li>
<li>Paris</li>
</settlement>
<orgName><li>Université Louis-et-Maximilien de Munich</li>
</orgName>
</list>
<tree><country name="Royaume-Uni"><noRegion><name sortKey="Lai, Yu Chiang" sort="Lai, Yu Chiang" uniqKey="Lai Y" first="Yu-Chiang" last="Lai">Yu-Chiang Lai</name>
</noRegion>
<name sortKey="Campbell, David G" sort="Campbell, David G" uniqKey="Campbell D" first="David G" last="Campbell">David G. Campbell</name>
<name sortKey="Dill, Brian D" sort="Dill, Brian D" uniqKey="Dill B" first="Brian D" last="Dill">Brian D. Dill</name>
<name sortKey="Gourlay, Robert" sort="Gourlay, Robert" uniqKey="Gourlay R" first="Robert" last="Gourlay">Robert Gourlay</name>
<name sortKey="Kondapalli, Chandana" sort="Kondapalli, Chandana" uniqKey="Kondapalli C" first="Chandana" last="Kondapalli">Chandana Kondapalli</name>
<name sortKey="Macartney, Thomas J" sort="Macartney, Thomas J" uniqKey="Macartney T" first="Thomas J" last="Macartney">Thomas J. Macartney</name>
<name sortKey="Muqit, Miratul Mk" sort="Muqit, Miratul Mk" uniqKey="Muqit M" first="Miratul Mk" last="Muqit">Miratul Mk Muqit</name>
<name sortKey="Peggie, Mark" sort="Peggie, Mark" uniqKey="Peggie M" first="Mark" last="Peggie">Mark Peggie</name>
<name sortKey="Procter, James B" sort="Procter, James B" uniqKey="Procter J" first="James B" last="Procter">James B. Procter</name>
<name sortKey="Trost, Matthias" sort="Trost, Matthias" uniqKey="Trost M" first="Matthias" last="Trost">Matthias Trost</name>
<name sortKey="Woodroof, Helen I" sort="Woodroof, Helen I" uniqKey="Woodroof H" first="Helen I" last="Woodroof">Helen I. Woodroof</name>
</country>
<country name="Allemagne"><region name="Bavière"><name sortKey="Lehneck, Ronny" sort="Lehneck, Ronny" uniqKey="Lehneck R" first="Ronny" last="Lehneck">Ronny Lehneck</name>
</region>
<name sortKey="Itzen, Aymelt" sort="Itzen, Aymelt" uniqKey="Itzen A" first="Aymelt" last="Itzen">Aymelt Itzen</name>
</country>
<country name="France"><region name="Île-de-France"><name sortKey="Corti, Olga" sort="Corti, Olga" uniqKey="Corti O" first="Olga" last="Corti">Olga Corti</name>
</region>
<name sortKey="Corvol, Jean Christophe" sort="Corvol, Jean Christophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name>
</country>
</tree>
</affiliations>
</record>
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