Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy
Robert Weil,
Emmanuel Laplantine,
Messaouda Attailia,
Anne Oudin,
Shannel Curic,
Aya Yokota,
Elie Banide,
Pierre Génin
Affiliations
Robert Weil
Centre d’Immunologie et des Maladies Infectieuses, CIMI-Paris, Sorbonne Université UMRS CR7 - Inserm U1135 - CNRS EMR8255, Faculté de Santé, 91 Boulevard de l’Hôpital, F-75013 Paris, France
Emmanuel Laplantine
Centre d’Immunologie et des Maladies Infectieuses, CIMI-Paris, Sorbonne Université UMRS CR7 - Inserm U1135 - CNRS EMR8255, Faculté de Santé, 91 Boulevard de l’Hôpital, F-75013 Paris, France
Messaouda Attailia
Université d’Orléans, UFR Sciences et Techniques, 45100 Orléans, France
Anne Oudin
Centre d’Immunologie et des Maladies Infectieuses, CIMI-Paris, Sorbonne Université UMRS CR7 - Inserm U1135 - CNRS EMR8255, Faculté de Santé, 91 Boulevard de l’Hôpital, F-75013 Paris, France
Shannel Curic
Université Paris-Saclay, Faculté de Médecine, 91190 Gif-sur-Yvette, France
Aya Yokota
Sorbonne Université, Faculté des Sciences et Ingénierie, 75005 Paris, France
Elie Banide
Université Paris-Saclay, Faculté de Médecine, 91190 Gif-sur-Yvette, France
Pierre Génin
Centre d’Immunologie et des Maladies Infectieuses, CIMI-Paris, Sorbonne Université UMRS CR7 - Inserm U1135 - CNRS EMR8255, Faculté de Santé, 91 Boulevard de l’Hôpital, F-75013 Paris, France; Corresponding author
Summary: Degradation of damaged mitochondria, a process called mitophagy, plays a role in mitochondrial quality control and its dysfunction has been linked to neurodegenerative pathologies. The PINK1 kinase and the ubiquitin ligase Parkin-mediated mitophagy represents the most common pathway in which specific receptors, including Optineurin (Optn), target ubiquitin-labeled mitochondria to autophagosomes. Here, we show that Protein Kinases D (PKD) are activated and recruited to damaged mitochondria. Subsequently, PKD phosphorylate Optn to promote a complex with Parkin leading to enhancement of its ubiquitin ligase activity. Paradoxically, inhibiting PKD activity enhances the interaction between Optn and LC3, promotes the recruitment of Parkin to mitochondria, and increases the mitophagic function of Optn. This enhancement of mitophagy is characterized by increased production of mitochondrial ROS and a reduction in mitochondrial mass. The PKD kinases may therefore regulate Optn-dependent mitophagy by amplifying the Parkin-mediated degradation signals to improve the cell response against oxidative stress damage.
