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Dynamic Phosphorylation of the C Terminus of Hsp70 Regulates the Mitochondrial Import of SOD2 and Redox Balance. Cell Rep 2018 11 27;25(9):2605-2616.e7

Date

11/30/2018

Pubmed ID

30485823

Pubmed Central ID

PMC6377235

DOI

10.1016/j.celrep.2018.11.015

Scopus ID

2-s2.0-85056969024   15 Citations

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-H2O2 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.

Author List

Zemanovic S, Ivanov MV, Ivanova LV, Bhatnagar A, Michalkiewicz T, Teng RJ, Kumar S, Rathore R, Pritchard KA Jr, Konduri GG, Afolayan AJ

Authors

Adeleye James Afolayan MD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Ru-Jeng Teng MD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Endothelial Cells
Enzyme Stability
Female
HEK293 Cells
HSP70 Heat-Shock Proteins
Humans
Hydrogen Peroxide
Mitochondria
Oxidation-Reduction
Phosphoprotein Phosphatases
Phosphorylation
Protein Binding
Protein Transport
Proteolysis
Proto-Oncogene Proteins c-akt
Rats, Sprague-Dawley
Serine
Sheep
Signal Transduction
Superoxide Dismutase
Ubiquitin-Protein Ligases
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a