1. Dynamic Phosphorylation of the C Terminus of Hsp70 Regulates the Mitochondrial Import of SOD2 and Redox Balance.
- Author
-
Zemanovic S, Ivanov MV, Ivanova LV, Bhatnagar A, Michalkiewicz T, Teng RJ, Kumar S, Rathore R, Pritchard KA Jr, Konduri GG, and Afolayan AJ
- Subjects
- Amino Acid Sequence, Animals, Endothelial Cells metabolism, Enzyme Stability, Female, HEK293 Cells, HSP70 Heat-Shock Proteins chemistry, Humans, Hydrogen Peroxide metabolism, Oxidation-Reduction, Phosphoprotein Phosphatases metabolism, Phosphorylation, Protein Binding, Protein Transport, Proteolysis, Proto-Oncogene Proteins c-akt metabolism, Rats, Sprague-Dawley, Serine metabolism, Sheep, Signal Transduction, Ubiquitin-Protein Ligases metabolism, HSP70 Heat-Shock Proteins metabolism, Mitochondria metabolism, Superoxide Dismutase metabolism
- Abstract
The import of superoxide dismutase-2 (SOD2) into mitochondria is vital for the survival of eukaryotic cells. SOD2 is encoded within the nuclear genome and translocated into mitochondria for activation after translation in the cytosol. The molecular chaperone Hsp70 modulates SOD2 activity by promoting import of SOD2 into mitochondria. In turn, the activity of Hsp70 is controlled by co-chaperones, particularly CHIP, which directs Hsp70-bound proteins for degradation in the proteasomes. We investigated the mechanisms controlling the activity of SOD2 to signal activation and maintain mitochondrial redox balance. We demonstrate that Akt1 binds to and phosphorylates the C terminus of Hsp70 on Serine631, which inhibits CHIP-mediated SOD2 degradation thereby stabilizing and promoting SOD2 import. Conversely, increased mitochondrial-H
2 O2 formation disrupts Akt1-mediated phosphorylation of Hsp70, and non-phosphorylatable Hsp70 mutants decrease SOD2 import, resulting in mitochondrial oxidative stress. Our findings identify Hsp70 phosphorylation as a physiological mechanism essential for regulation of mitochondrial redox balance., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF