SIRT1 Protects the Heart from ER Stress-Induced Injury by Promoting eEF2K/eEF2-Dependent Autophagy.

Julie Pires Da Silva,Christophe Lemaire,Arnaud Guilbert,Kevin Monceaux,Renée Ventura-Clapier,Anne Garnier,Mélanie Gressette,Jérôme Piquereau,Marta Novotova

doi:10.3390/cells9020426

Julie Pires Da Silva, Christophe Lemaire + Show 7 more

Open Access

https://doi.org/10.3390/cells9020426

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Abstract

Many recent studies have demonstrated the involvement of endoplasmic reticulum (ER) stress in the development of cardiac diseases and have suggested that modulation of ER stress response could be cardioprotective. Previously, we demonstrated that the deacetylase Sirtuin 1 (SIRT1) attenuates ER stress response and promotes cardiomyocyte survival. Here, we investigated whether and how autophagy plays a role in SIRT1-afforded cardioprotection against ER stress. The results revealed that protective autophagy was initiated before cell death in response to tunicamycin (TN)-induced ER stress in cardiac cells. SIRT1 inhibition decreased ER stress-induced autophagy, whereas its activation enhanced autophagy. In response to TN- or isoproterenol-induced ER stress, mice deficient for SIRT1 exhibited suppressed autophagy along with exacerbated cardiac dysfunction. At the molecular level, we found that in response to ER stress (i) the extinction of eEF2 or its kinase eEF2K not only reduced autophagy but further activated cell death, (ii) inhibition of SIRT1 inhibited the phosphorylation of eEF2, (iii) eIF2α co-immunoprecipitated with eEF2K, and (iv) knockdown of eIF2α reduced the phosphorylation of eEF2. Our results indicate that in response to ER stress, SIRT1 activation promotes cardiomyocyte survival by enhancing autophagy at least through activation of the eEF2K/eEF2 pathway.

Highlights

The endoplasmic reticulum (ER) coordinates the synthesis, folding, and quality control of almost all secreted and membrane proteins
We have previously shown that Sirtuin 1 (SIRT1) protects cardiomyocytes against ER stress-induced apoptosis by regulating the activation of the PERK pathway of the unfolded protein response (UPR) [12]
As we demonstrated that SIRT1 regulates autophagy/mitophagy and cell death in cardiac cells in response to ER stress, we hypothesized that this regulation might involve the eEF2K/eukaryotic elongation factor-2 (eEF2) pathway

Summary

Introduction

The endoplasmic reticulum (ER) coordinates the synthesis, folding, and quality control of almost all secreted and membrane proteins. The UPR is initiated by the activation of three proximal sensors, namely ATF6, IRE1, and PERK. Activation of these sensors leads to transcriptional and translational reprogramming to cope with the accumulation of unfolded proteins by reducing the translation of non-UPR proteins and upregulating the expression of UPR-related proteins such as ER chaperones, proteins that participate in ER-associated protein degradation (ERAD), Cells 2020, 9, 426; doi:10.3390/cells9020426 www.mdpi.com/journal/cells. In the case of severe or chronic ER stress, if ER homeostasis fails to be reestablished, UPR assumes an adverse role and triggers the intrinsic pathway of apoptosis to eliminate damaged cells [2,3]

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