2. Academic Validation
  3. A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy

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

  • J Cell Biol. 2024 Jul 1;223(7):e202309015. doi: 10.1083/jcb.202309015.
Dan A Tudorica 1 2 3,  Bishal Basak 1 4,  Alexia S Puerta Cordova 3 5,  Grace Khuu 1 6,  Kevin Rose 3 5,  Michael Lazarou 1 6,  Erika L F Holzbaur 1 4,  James H Hurley 1 2 3 7
Affiliations

Affiliations

  • 1 Aligning Science Across Parkinson's (ASAP) Collaborative Research Network , Chevy Chase, MD, USA.
  • 2 Graduate Group in Biophysics, University of California, Berkeley, Berkeley, CA, USA.
  • 3 California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
  • 4 Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 5 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 6 Walter and Eliza Hall Institute of Medical Research , Melbourne, Australia.
  • 7 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
PMID: 38728007 DOI: 10.1083/jcb.202309015
Abstract

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.

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