A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy.

Mitophagy / genetics Humans rab7 GTP-Binding Proteins Phosphorylation Ubiquitin-Protein Ligases / metabolism Protein Serine-Threonine Kinases / metabolism rab GTP-Binding Proteins / metabolism HeLa Cells Protein Binding Intracellular Signaling Peptides and Proteins / metabolism Autophagy-Related Proteins / metabolism Mitochondria / metabolism HEK293 Cells

Journal

The Journal of cell biology
ISSN: 1540-8140
Titre abrégé: J Cell Biol
Pays: United States
ID NLM: 0375356

Informations de publication

Date de publication:
01 Jul 2024
Historique:
received: 05 09 2023
revised: 12 01 2024
accepted: 05 04 2024
medline: 10 5 2024
pubmed: 10 5 2024
entrez: 10 5 2024
Statut: ppublish

Résumé

Activation of PINK1 and Parkin in response to mitochondrial damage initiates a response that includes phosphorylation of RAB7A at Ser72. Rubicon is a RAB7A binding negative regulator of autophagy. The structure of the Rubicon:RAB7A complex suggests that phosphorylation of RAB7A at Ser72 would block Rubicon binding. Indeed, in vitro phosphorylation of RAB7A by TBK1 abrogates Rubicon:RAB7A binding. Pacer, a positive regulator of autophagy, has an RH domain with a basic triad predicted to bind an introduced phosphate. Consistent with this, Pacer-RH binds to phosho-RAB7A but not to unphosphorylated RAB7A. In cells, mitochondrial depolarization reduces Rubicon:RAB7A colocalization whilst recruiting Pacer to phospho-RAB7A-positive puncta. Pacer knockout reduces Parkin mitophagy with little effect on bulk autophagy or Parkin-independent mitophagy. Rescue of Parkin-dependent mitophagy requires the intact pRAB7A phosphate-binding basic triad of Pacer. Together these structural and functional data support a model in which the TBK1-dependent phosphorylation of RAB7A serves as a switch, promoting mitophagy by relieving Rubicon inhibition and favoring Pacer activation.

Identifiants

DOI: 10.1083/jcb.202309015 PMID: 38728007
pubmed: 38728007
pii: 276747
doi: 10.1083/jcb.202309015
pii:
doi:

Substances chimiques

parkin protein EC 2.3.2.27
rab7 GTP-Binding Proteins 0
Ubiquitin-Protein Ligases EC 2.3.2.27
Protein Serine-Threonine Kinases EC 2.7.11.1
rab GTP-Binding Proteins EC 3.6.5.2
rab7 GTP-binding proteins, human 0
RUBCN protein, human 0
TBK1 protein, human EC 2.7.11.1
Intracellular Signaling Peptides and Proteins 0
Autophagy-Related Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Aligning Science Across Parkinson's
ID : ASAP-000350

Informations de copyright

© 2024 Tudorica et al.

Auteurs

Dan A Tudorica (DA)

Aligning Science Across Parkinson's (ASAP) Collaborative Research Network , Chevy Chase, MD, USA.
Graduate Group in Biophysics, University of California, Berkeley, Berkeley, CA, USA.
California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0003-0337-5150

Bishal Basak (B)

Aligning Science Across Parkinson's (ASAP) Collaborative Research Network , Chevy Chase, MD, USA.
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0003-4496-4162

Alexia S Puerta Cordova (AS)

California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0003-2455-9776

Grace Khuu (G)

Aligning Science Across Parkinson's (ASAP) Collaborative Research Network , Chevy Chase, MD, USA.
Walter and Eliza Hall Institute of Medical Research , Melbourne, Australia.
ORCID: 0000-0002-2550-0605

Kevin Rose (K)

California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0002-9373-4147

Michael Lazarou (M)

Aligning Science Across Parkinson's (ASAP) Collaborative Research Network , Chevy Chase, MD, USA.
Walter and Eliza Hall Institute of Medical Research , Melbourne, Australia.
ORCID: 0000-0003-2150-5545

Erika L F Holzbaur (ELF)

Aligning Science Across Parkinson's (ASAP) Collaborative Research Network , Chevy Chase, MD, USA.
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0001-5389-4114

James H Hurley (JH)

Aligning Science Across Parkinson's (ASAP) Collaborative Research Network , Chevy Chase, MD, USA.
Graduate Group in Biophysics, University of California, Berkeley, Berkeley, CA, USA.
California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0001-5054-5445

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Classifications MeSH

questionsmedicales.fr › Phénomènes physiologiques cellulaires › Renouvellement des mitochondries › Dégradation des mitochondries › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines G › Protéines G monomériques › Protéines G rab › Protéines Rab7 liant le GTP › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Métabolisme › Phosphorylation › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Ligases › Ubiquitin-protein ligase complexes › Ubiquitin-protein ligases › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines G › Protéines G monomériques › Protéines G rab › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HeLa › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Métabolisme › Liaison aux protéines › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à l'autophagie › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › A RAB7A phosphoswitch coordinates Rubicon...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › A RAB7A phosphoswitch coordinates Rubicon...