Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies

Main, A. et al. (2022) Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies. Frontiers in Physiology, 13, 1023237. (doi: 10.3389/fphys.2022.1023237)

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Abstract

S-palmitoylation is an essential lipid modification catalysed by zDHHC-palmitoyl acyltransferases that regulates the localisation and activity of substrates in every class of protein and tissue investigated to date. In the heart, S-palmitoylation regulates sodium-calcium exchanger (NCX1) inactivation, phospholemman (PLM) inhibition of the Na+/K+ ATPase, Nav1.5 influence on membrane excitability and membrane localisation of heterotrimeric G-proteins. The cell surface localised enzyme zDHHC5 palmitoylates NCX1 and PLM and is implicated in injury during anoxia/reperfusion. Little is known about how palmitoylation remodels in cardiac diseases. We investigated expression of zDHHC5 in animal models of left ventricular hypertrophy (LVH) and heart failure (HF), along with HF tissue from humans. zDHHC5 expression increased rapidly during onset of LVH, whilst HF was associated with decreased zDHHC5 expression. Paradoxically, palmitoylation of the zDHHC5 substrate NCX1 was significantly reduced in LVH but increased in human HF, while palmitoylation of the zDHHC5 substrate PLM was unchanged in all settings. Overexpression of zDHHC5 in rabbit ventricular cardiomyocytes did not alter palmitoylation of its substrates or overall cardiomyocyte contractility, suggesting changes in zDHHC5 expression in disease may not be a primary driver of pathology. zDHHC5 itself is regulated by post-translational modifications, including palmitoylation in its C-terminal tail. We found that in HF palmitoylation of zDHHC5 changed in the same manner as palmitoylation of NCX1, suggesting additional regulatory mechanisms may be involved. This study provides novel evidence that palmitoylation of cardiac substrates is altered in the setting of HF, and that expression of zDHHC5 is dysregulated in both hypertrophy and HF.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fuller, Professor Will and Main, Alice and Kuo, Dr Chien-Wen and Rankin, Mrs Aileen and Smith, Professor Godfrey and Baillie, Professor George and Howie, Dr Jacqueline and Burton, Dr Francis
Authors: Main, A., Bogusalvskyii, A., Howie, J., Kuo, C.-W., Rankin, A., Burton, F. L., Smith, G. L., Hajjar, R., Baillie, G. S., Campbell, K. S., Shattock, M. J., and Fuller, W.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Frontiers in Physiology
Publisher:Frontiers Media
ISSN:1664-042X
ISSN (Online):1664-042X
Copyright Holders:Copyright © 2022 Main, Boguslavskyi, Howie, Kuo, Rankin, Burton, Smith, Hajjar, Baillie, Campbell, Shattock and Fuller
First Published:First published in Frontiers in Physiology 13: 1023237
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303370The role of NCX1 palmitoylation in cardiac functionWilliam FullerBritish Heart Foundation (BHF)SP/16/3/32317CAMS - Cardiovascular Science
304319Palmitoylation of the L-Type Ca Channel Pore-Forming SubunitWilliam FullerBritish Heart Foundation (BHF)PG/18/60/33957CAMS - Cardiovascular Science
301690The Na/K ATPase in cardiovascular health and diseaseWilliam FullerBritish Heart Foundation (BHF)RE12627 - RG/17/15/33106CAMS - Cardiovascular Science
303944BHF Centre of ExcellenceColin BerryBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science