title: SIRT1 protects the heart from ER stress-induced cell death through eIF2α deacetylation.
abstract: Over the past decade, endoplasmic reticulum (ER) stress has emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. Cardiac therapy based on ER stress modulation is viewed as a promising avenue toward effective therapies for the diseased heart. Here, we tested whether sirtuin-1 (SIRT1), a NAD+-dependent deacetylase, participates in modulating ER stress response in the heart. Using cardiomyocytes and adult-inducible SIRT1 knockout mice, we demonstrate that SIRT1 inhibition or deficiency increases ER stress-induced cardiac injury, whereas activation of SIRT1 by the SIRT1-activating compound STAC-3 is protective. Analysis of the expression of markers of the three main branches of the unfolded protein response (i.e., PERK/eIF2α, ATF6 and IRE1) showed that SIRT1 protects cardiomyocytes from ER stress-induced apoptosis by attenuating PERK/eIF2α pathway activation. We also present evidence that SIRT1 physically interacts with and deacetylates eIF2α. Mass spectrometry analysis identified lysines K141 and K143 as the acetylation sites on eIF2α targeted by SIRT1. Furthermore, mutation of K143 to arginine to mimic eIF2α deacetylation confers protection against ER stress-induced apoptosis. Collectively, our findings indicate that eIF2α deacetylation on lysine K143 by SIRT1 is a novel regulatory mechanism for protecting cardiac cells from ER stress and suggest that activation of SIRT1 has potential as a therapeutic approach to protect the heart against ER stress-induced injury.
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prola
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Pires Da Silva
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Guilbert
authors.affiliation: UMR-S 1014, INSERM, Univ Paris-Sud, Université Paris-Saclay, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Lola
authors.initials: L
authors.lastname: Lecru
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Piquereau
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Maxance
authors.initials: M
authors.lastname: Ribeiro
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Mateo
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gressette
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Fortin
authors.affiliation: Institut Paris-Sud d'Innovation Thérapeutique, Univ Paris-Sud, Université Paris-Saclay, Chatenay-Malabry, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Boursier
authors.affiliation: UMR-S 1014, INSERM, Univ Paris-Sud, Université Paris-Saclay, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Gallerne
authors.affiliation: UMR-S 942, INSERM, Univ Denis Diderot, Hôpital Lariboisière, Paris, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Caillard
authors.affiliation: UMR-S 942, INSERM, Univ Denis Diderot, Hôpital Lariboisière, Paris, France.
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.affiliation: UMR-S 1014, INSERM, Univ Paris-Sud, Université Paris-Saclay, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: François
authors.affiliation: Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA, USA.|Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.affiliation: UMR-S 1014, INSERM, Univ Paris-Sud, Université Paris-Saclay, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Eid
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Garnier
authors.affiliation: UMR-S 1180, INSERM, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.|Université Versailles St. Quentin, Université Paris-Saclay, Versailles, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lemaire
mesh_terms: D000107:Acetylation; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D002227:Carbazoles; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C053387:endoplasmin; D014415:Tunicamycin; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D056564:Sirtuin 1