Glutathione-dependent depalmitoylation of phospholemman by peroxiredoxin 6

Howie, J. et al. (2024) Glutathione-dependent depalmitoylation of phospholemman by peroxiredoxin 6. Cell Reports, 43(2), 113679. (doi: 10.1016/j.celrep.2024.113679) (PMID:38236777)

Abstract

Phospholemman (PLM) regulates the cardiac sodium pump: PLM phosphorylation activates the pump whereas PLM palmitoylation inhibits its activity. Here, we show that the anti-oxidant protein peroxiredoxin 6 (Prdx6) interacts with and depalmitoylates PLM in a glutathione-dependent manner. Glutathione loading cells acutely reduce PLM palmitoylation; glutathione depletion significantly increases PLM palmitoylation. Prdx6 silencing abolishes these effects, suggesting that PLM can be depalmitoylated by reduced Prdx6. In vitro, only recombinant Prdx6, among several peroxiredoxin isoforms tested, removes palmitic acid from recombinant palmitoylated PLM. The broad-spectrum depalmitoylase inhibitor palmostatin B prevents Prdx6-dependent PLM depalmitoylation in cells and in vitro. Our data suggest that Prdx6 is a thioesterase that can depalmitoylate proteins by nucleophilic attack via its reactive thiol, linking PLM palmitoylation and hence sodium pump activity to cellular glutathione status. We show that protein depalmitoylation can occur via a catalytic cysteine in which substrate specificity is determined by a protein-protein interaction.

• Item Type: Articles
• Additional Information: This work was supported by the British Heart Foundation with grants RG/07/001 and RG/12/4/29426 awarded to MJS and WF, RG/17/15/33106 to MJS, NJF and WF, and FS/13/22/30126 to WF.
• Status: Published
• Refereed: No
• Glasgow Author(s) Enlighten ID: Howie, Dr Jacqueline and Fuller, Professor Will and Wypijewski, Mr Krzysztof and Brown, Miss Elaine

Creator Roles

Fuller, W.: Conceptualization, Methodology, Writing – original draft, Supervision, Project administration, Funding acquisition
Howie, J.: Methodology, Investigation
Brown, E.: Investigation
Wypijewski, K.: Investigation

• Authors: Howie, J., Tulloch, L. B., Brown, E., Reilly, L., Ashford, F. B., Kennedy, J., Wypijewski, K. J., Aughton, K. L., Mak, J. K.C., Shattock, M. J., Fraser, N. J., and Fuller, W.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• Copyright Holders: Copyright: © 2024 The Authors
• First Published: First published in Cell Reports 43(2): 113679
• Publisher Policy: Reproduced under a Creative Commons licence

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
301690		The Na/K ATPase in cardiovascular health and disease	William Fuller	British Heart Foundation (BHF)	RE12627 - RG/17/15/33106	SCMH - Cardiovascular & Metabolic Health