Mitochondrial diacylglycerol initiates protein-kinase D1-mediated ROS signaling.
Increases in reactive oxygen species (ROS) have been implicated in age-related diseases, including cancer. The serine/threonine kinase protein kinase D1 (PKD1) is a stress-responsive kinase and sensor for reactive oxygen species, which can initiate cell survival through NF-kappaB signaling. We have previously shown that in response to ROS, PKD1 is activated at the mitochondria. However, the initial signaling events leading to localization of PKD1 to the mitochondria are unknown. Here, we show that formation of mitochondrial diacylglycerol (DAG) and its binding to PKD1 is the means by which PKD1 is localized to the mitochondria in response to ROS. Interestingly, DAG to which PKD1 is recruited in this pathway is formed downstream of phospholipase D1 (PLD1) and a lipase-inactive PLD1 or inhibition of PLD1 by pharmacological inhibitors blocked PKD1 activation under oxidative stress. To date it has been viewed that monosaturated and saturated DAG formed via PLD1 have no signaling function. However, our data describe a role for PLD1-induced DAG as a competent second messenger at the mitochondria that relays ROS to PKD1-mediated mitochondria-to-nucleus signaling.
Cowell
Catherine F
CF
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL 32224, USA.
Döppler
Heike
H
Yan
Irene K
IK
Hausser
Angelika
A
Umezawa
Yoshio
Y
Storz
Peter
P
D001665:Binding Sites; D055162:Biocatalysis; D004075:Diglycerides / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress; D010739:Phospholipase D / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
D004075:Diglycerides; D050505:Mutant Proteins; D017382:Reactive Oxygen Species; D019000:Phosphotyrosine; C089212:protein kinase D; D019061:src-Family Kinases; D011493:Protein Kinase C; D010739:Phospholipase D; C106801:phospholipase D1