Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies
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) inactivatio...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.1023237/full |
| _version_ | 1828727761171120128 |
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| author | Alice Main Andri Boguslavskyi Jacqueline Howie Chien-Wen Kuo Aileen Rankin Francis L. Burton Godfrey L. Smith Roger Hajjar George S. Baillie Kenneth S. Campbell Michael J. Shattock William Fuller |
| author_facet | Alice Main Andri Boguslavskyi Jacqueline Howie Chien-Wen Kuo Aileen Rankin Francis L. Burton Godfrey L. Smith Roger Hajjar George S. Baillie Kenneth S. Campbell Michael J. Shattock William Fuller |
| author_sort | Alice Main |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T14:03:12Z |
| format | Article |
| id | doaj.art-7cbe5c5a5f744ee8954ab054d0919e50 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-12T14:03:12Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-7cbe5c5a5f744ee8954ab054d0919e502022-12-22T03:30:09ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-10-011310.3389/fphys.2022.10232371023237Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologiesAlice Main0Andri Boguslavskyi1Jacqueline Howie2Chien-Wen Kuo3Aileen Rankin4Francis L. Burton5Godfrey L. Smith6Roger Hajjar7George S. Baillie8Kenneth S. Campbell9Michael J. Shattock10William Fuller11Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United KingdomSchool of Cardiovascular and Metabolic Medicine and Sciences, King’s College London, London, United KingdomInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United KingdomInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United KingdomInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United KingdomInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United KingdomInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United KingdomFlagship Pioneering, Cambridge, MA, United StatesInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United KingdomDivision of Cardiovascular Medicine, University of Kentucky, Lexington, KY, United StatesSchool of Cardiovascular and Metabolic Medicine and Sciences, King’s College London, London, United KingdomInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United KingdomS-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.https://www.frontiersin.org/articles/10.3389/fphys.2022.1023237/fullpalmitoylationhypertrophyheart failureZDHHC5cardiac muscledepalmitoylation |
| spellingShingle | Alice Main Andri Boguslavskyi Jacqueline Howie Chien-Wen Kuo Aileen Rankin Francis L. Burton Godfrey L. Smith Roger Hajjar George S. Baillie Kenneth S. Campbell Michael J. Shattock William Fuller Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies Frontiers in Physiology palmitoylation hypertrophy heart failure ZDHHC5 cardiac muscle depalmitoylation |
| title | Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies |
| title_full | Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies |
| title_fullStr | Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies |
| title_full_unstemmed | Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies |
| title_short | Dynamic but discordant alterations in zDHHC5 expression and palmitoylation of its substrates in cardiac pathologies |
| title_sort | dynamic but discordant alterations in zdhhc5 expression and palmitoylation of its substrates in cardiac pathologies |
| topic | palmitoylation hypertrophy heart failure ZDHHC5 cardiac muscle depalmitoylation |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.1023237/full |
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