Insights into the molecular basis of the palmitoylation and depalmitoylation of NCX1

Gök, Çağlar; Main, Alice; Gao, Xing; Kerekes, Zsombor; Plain, Fiona; Kuo, Chien-Wen; Robertson, Alan D.; Fraser, Niall J.; Fuller, William

doi:10.1016/j.ceca.2021.102408

Cited by 15 publications

(11 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several depalmitoylating enzymes show altered expression in both HFrEF and HFpEF, although not to the same extent as the dysregulated of zDHHC-PAT expression ( Figure 1 ). In comparison to zDHHC-PATs, relatively little is known about the regulation of these enzymes, although APT1 was recently demonstrated to depalmitoylate NCX1 ( Gök et al, 2021 ). However, we did not find a significant change in APT1 protein abundance in the setting of HF, so this likely does not explain the changes in substrate palmitoylation observed ( Supplementary Figure S5 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several depalmitoylating enzymes show altered expression in both HFrEF and HFpEF, although perhaps to not the same extent as the dysregulated of zDHHC-PAT expression (Figure 1). In comparison to zDHHC-PATs, relatively little is known about the regulation of these enzymes, although APT1 was recently demonstrated to depalmitoylate NCX1 (Gök et al ., 2021). However, we did not find a significant change in APT1 protein abundance in the setting of HF, so this likely does not explain the changes in substrate palmitoylation observed (Supplementary Figure 4).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, despite RNA sequencing data suggesting zDHHC5 expression levels are reduced in HFpEF but unchanged in HFrEF (Figure 1; Hahn et al, 2021) we found that protein expression of zDHHC5 was also significantly reduced in ischaemic HF samples compared to organ donors (Figure 5). We also investigated the expression of thioesterase APT1, which depalmitoylates NCX1, but found there was no significant change in expression in these samples (Supplementary Figure 4; Gök et al, 2021). Given both animal models and human HF samples were associated with reduced zDHHC5 expression, we investigated whether this correlated with a change in the palmitoylation of zDHHC5 substrates NCX1 and PLM.…”

Section: Zdhhc5 In Heart Failurementioning

confidence: 99%

zDHHC5 expression is increased in cardiac hypertrophy and reduced in heart failure but this does not correlate with changes in substrate palmitoylation

Main

Boguslavskyi

Howie

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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. Information is lacking 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 was rapidly elevated 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. Overexpression of zDHHC5 in rabbit ventricular cardiomyocytes was not sufficient to drive changes in palmitoylation of zDHHC5 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, and we found the palmitoylation of zDHHC5 may be increased in heart failure in the same manner as NCX1, suggesting additional regulatory mechanisms such as acyl-CoA availability may be involved. Importantly, this study provides the first 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.

show abstract

“…On the other hand, palmitoylation affects the channel affinity for LRs, triggering an increase in transmembrane Ca 2+ flux [ 44 ]. Because NCX1 is crucial in the regulation of Ca 2+ transport, upon control of transmembrane Na + gradients, altering palmitoylation may provide benefits in the study of the immunological consequences of elevated cytosolic Ca 2+ levels [ 45 ]. Therefore, palmitoylation undertakes central functions in ion channel regulation.…”

Section: S -Palmitoylation Of Ion Channelsmentioning

confidence: 99%

Palmitoylation of Voltage-Gated Ion Channels

Cassinelli

Viñola-Renart

Benavente-Garcia

et al. 2022

IJMS

View full text Add to dashboard Cite

Protein lipidation is one of the most common forms of posttranslational modification. This alteration couples different lipids, such as fatty acids, phospho- and glycolipids and sterols, to cellular proteins. Lipidation regulates different aspects of the protein’s physiology, including structure, stability and affinity for cellular membranes and protein–protein interactions. In this scenario, palmitoylation is the addition of long saturated fatty acid chains to amino acid residues of the proteins. The enzymes responsible for this modification are acyltransferases and thioesterases, which control the protein’s behavior by performing a series of acylation and deacylation cycles. These enzymes target a broad repertoire of substrates, including ion channels. Thus, protein palmitoylation exhibits a pleiotropic role by differential modulation of the trafficking, spatial organization and electrophysiological properties of ion channels. Considering voltage-gated ion channels (VGICs), dysregulation of lipidation of both the channels and the associated ancillary subunits correlates with the development of various diseases, such as cancer or mental disorders. Therefore, a major role for protein palmitoylation is currently emerging, affecting not only the dynamism and differential regulation of a moiety of cellular proteins but also linking to human health. Therefore, palmitoylation of VGIC, as well as related enzymes, constitutes a novel pharmacological tool for drug development to target related pathologies.

show abstract

Insights into the molecular basis of the palmitoylation and depalmitoylation of NCX1

Abstract: Graphical abstract

Cited by 15 publications

References 44 publications

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

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

zDHHC5 expression is increased in cardiac hypertrophy and reduced in heart failure but this does not correlate with changes in substrate palmitoylation

Palmitoylation of Voltage-Gated Ion Channels

Contact Info

Product

Resources

About