Disruption of protein quality control of the human ether-à-go-go related gene K+ channel results in profound long QT syndrome
Published by Elsevier Inc..
BACKGROUND: Long QT syndrome (LQTS) is a hereditary disease that predisposes patients to life-threatening cardiac arrhythmias and sudden cardiac death. Our previous study of the human ether-à-go-go related gene (hERG)-encoded K+ channel (Kv11.1) supports an association between hERG and RING finger protein 207 (RNF207) variants in aggravating the onset and severity of LQTS, specifically T613M hERG (hERGT613M) and RNF207 frameshift (RNF207G603fs) mutations. However, the underlying mechanistic underpinning remains unknown.
OBJECTIVE: The purpose of the present study was to test the role of RNF207 in the function of hERG-encoded K+ channel subunits.
METHODS: Whole-cell patch-clamp experiments were performed in human embryonic kidney (HEK 293) cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) together with immunofluorescent confocal and high resolution microscopy, auto-ubiquitinylation assays, and co-immunoprecipitation experiments to test the functional interactions between hERG and RNF207.
RESULTS: Here, we demonstrated that RNF207 serves as an E3 ubiquitin ligase and targets misfolded hERGT613M proteins for degradation. RNF207G603fs exhibits decreased activity and hinders the normal degradation pathway; this increases the levels of hERGT613M subunits and their dominant-negative effect on the wild-type subunits, ultimately resulting in decreased current density. Similar findings are shown for hERGA614V, a known dominant-negative mutant subunit. Finally, the presence of RNF207G603fs with hERGT613M results in significantly prolonged action potential durations and reduced hERG current in human-induced pluripotent stem cell-derived cardiomyocytes.
CONCLUSION: Our study establishes RNF207 as an interacting protein serving as a ubiquitin ligase for hERG-encoded K+ channel subunits. Normal function of RNF207 is critical for the quality control of hERG subunits and consequently cardiac repolarization. Moreover, our study provides evidence for protein quality control as a new paradigm in life-threatening cardiac arrhythmias in patients with LQTS.
| Errataetall: |
CommentIn: Heart Rhythm. 2022 Feb;19(2):293-294. - PMID 34687922 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
Heart rhythm - 19(2022), 2 vom: 20. Feb., Seite 281-292 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ledford, Hannah A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.03.2022 Date Revised 14.03.2022 published: Print-Electronic CommentIn: Heart Rhythm. 2022 Feb;19(2):293-294. - PMID 34687922 Citation Status MEDLINE |
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| doi: |
10.1016/j.hrthm.2021.10.005 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM331753383 |
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| 100 | 1 | |a Ledford, Hannah A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Disruption of protein quality control of the human ether-à-go-go related gene K+ channel results in profound long QT syndrome |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 14.03.2022 | ||
| 500 | |a Date Revised 14.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Heart Rhythm. 2022 Feb;19(2):293-294. - PMID 34687922 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Published by Elsevier Inc. | ||
| 520 | |a BACKGROUND: Long QT syndrome (LQTS) is a hereditary disease that predisposes patients to life-threatening cardiac arrhythmias and sudden cardiac death. Our previous study of the human ether-à-go-go related gene (hERG)-encoded K+ channel (Kv11.1) supports an association between hERG and RING finger protein 207 (RNF207) variants in aggravating the onset and severity of LQTS, specifically T613M hERG (hERGT613M) and RNF207 frameshift (RNF207G603fs) mutations. However, the underlying mechanistic underpinning remains unknown | ||
| 520 | |a OBJECTIVE: The purpose of the present study was to test the role of RNF207 in the function of hERG-encoded K+ channel subunits | ||
| 520 | |a METHODS: Whole-cell patch-clamp experiments were performed in human embryonic kidney (HEK 293) cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) together with immunofluorescent confocal and high resolution microscopy, auto-ubiquitinylation assays, and co-immunoprecipitation experiments to test the functional interactions between hERG and RNF207 | ||
| 520 | |a RESULTS: Here, we demonstrated that RNF207 serves as an E3 ubiquitin ligase and targets misfolded hERGT613M proteins for degradation. RNF207G603fs exhibits decreased activity and hinders the normal degradation pathway; this increases the levels of hERGT613M subunits and their dominant-negative effect on the wild-type subunits, ultimately resulting in decreased current density. Similar findings are shown for hERGA614V, a known dominant-negative mutant subunit. Finally, the presence of RNF207G603fs with hERGT613M results in significantly prolonged action potential durations and reduced hERG current in human-induced pluripotent stem cell-derived cardiomyocytes | ||
| 520 | |a CONCLUSION: Our study establishes RNF207 as an interacting protein serving as a ubiquitin ligase for hERG-encoded K+ channel subunits. Normal function of RNF207 is critical for the quality control of hERG subunits and consequently cardiac repolarization. Moreover, our study provides evidence for protein quality control as a new paradigm in life-threatening cardiac arrhythmias in patients with LQTS | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Cardiac ion channels | |
| 650 | 4 | |a E3 ubiquitin ligase | |
| 650 | 4 | |a Endoplasmic reticulum-associated degradation | |
| 650 | 4 | |a Human ether a-go-go related gene (hERG)–encoded potassium channels | |
| 650 | 4 | |a Human induced pluripotent stem cell-derived cardiomyocytes | |
| 650 | 4 | |a Human induced pluripotent stem cells | |
| 650 | 4 | |a Long QT syndrome | |
| 650 | 4 | |a Protein quality control | |
| 650 | 4 | |a RING finger protein 207 (RNF207) | |
| 650 | 7 | |a ERG1 Potassium Channel |2 NLM | |
| 650 | 7 | |a RNF207 protein, human |2 NLM | |
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| 650 | 7 | |a Ubiquitin-Protein Ligases |2 NLM | |
| 650 | 7 | |a EC 2.3.2.27 |2 NLM | |
| 700 | 1 | |a Ren, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Thai, Phung N |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Seojin |e verfasserin |4 aut | |
| 700 | 1 | |a Timofeyev, Valeriy |e verfasserin |4 aut | |
| 700 | 1 | |a Sirish, Padmini |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Wilson |e verfasserin |4 aut | |
| 700 | 1 | |a Emigh, Aiyana M |e verfasserin |4 aut | |
| 700 | 1 | |a Priest, James R |e verfasserin |4 aut | |
| 700 | 1 | |a Perez, Marco V |e verfasserin |4 aut | |
| 700 | 1 | |a Ashley, Euan A |e verfasserin |4 aut | |
| 700 | 1 | |a Yarov-Yarovoy, Vladimir |e verfasserin |4 aut | |
| 700 | 1 | |a Yamoah, Ebenezer N |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiao-Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Chiamvimonvat, Nipavan |e verfasserin |4 aut | |
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