Dynamic Phosphorylation of the C Terminus of Hsp70 Regulates the Mitochondrial Import of SOD2 and Redox Balance

Abstract

SUMMARY 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.

Post-translational modifications of Hsp70 family proteins: Expanding the chaperone code

“…Loss of this phosphorylation has the converse effect, triggering enhanced client degradation resulting from Hsp70-CHIP interaction (58). Similarly, another study demonstrated that the SBD of Hsp70 is phosphorylated by Akt1 at Ser-631, which decreases Hsp70-CHIP interaction (78). In this report, the downstream effect observed was to prevent degradation of superoxide dismutase-2 (SOD2) and promote the import of SOD2 into the mitochondria.…”

NKT-like cells reveal higher than T lymphocytes expression of cellular protective proteins HSP70 and SOD2 and comparably increased expression of SIRT1 in the oldest seniors

“…glutathione (GSH) [18][19][20][21]. Continuous low-dose oxidative stress during ageing results in adaptive responses based on the activation of NF-kB and subsequently superoxide dismutases (SODs) with a key role played by the mitochondrial manganese superoxide dismutase (SOD2) [22,23]. In this process also heat-shock proteins (e.g.…”

A ratiometric fluorescent probe for detecting the endogenous biological signaling molecule superoxide anion and bioimaging during tumor treatment

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