Academic Journal
Transmembrane protein 168 mutation reduces cardiomyocyte cell surface expression of Nav1.5 through αB-crystallin intracellular dynamics.
| العنوان: | Transmembrane protein 168 mutation reduces cardiomyocyte cell surface expression of Nav1.5 through αB-crystallin intracellular dynamics. |
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| المؤلفون: | NGUYEN Le Kim Chi, SHIMIZU Akio, SOH Joanne Ern Chi, KOMENO Masahiro, SATO Akira, 扇田 久和, 清水 昭男, 米野 雅大, 佐藤 朗 |
| بيانات النشر: | Oxford University Press |
| سنة النشر: | 2021 |
| المجموعة: | Shiga University of Medical Science Repository BI WAKO / 滋賀医科大学機関リポジトリ |
| مصطلحات موضوعية: | Brugada syndrome, heat shock protein, protein interaction, sodium channel, ubiquitination |
| الوصف: | Transmembrane protein 168 (TMEM168) was found to be localized on the nuclear membrane. A heterozygous mutation (c.1616G>A, p. R539Q) in TMEM168 was identified in patients with Brugada syndrome. This mutation reduced expression of cardiomyocyte sodium channel Nav1.5 via Nedd4-2 E3 ubiquitin ligase-induced ubiquitination and degradation. However, the detailed molecular mechanism provoked by the TMEM168 mutant remains unclear. Here, we demonstrated that small heat shock protein αB-crystallin, which can bind to Nav1.5 and Nedd4-2 and interfere with the association of both proteins, was strongly recruited from the cell surface to the perinuclear region because of the much higher affinity of αB-crystallin with the TMEM168 mutant than with wild-type TMEM168. Following knockdown of αB-crystallin in HL-1 cardiomyocytes, the interaction of Nav1.5 with Nedd4-2 was increased, despite the reduced expression of Nav1.5. Moreover, reduction of Nav1.5 expression by αB-crystallin knockdown was rescued in the presence of a proteasome inhibitor MG-132, suggesting the importance of the αB-crystallin-modulated ubiquitin-proteasome system for the stability of Nav1.5 expression. Collectively, the balance of molecular interactions among Nav1.5, Nedd4-2 and αB-crystallin plays a role in the regulation of cardiomyocyte cell surface expression of Nav1.5, and the TMEM168 mutant disturbs this balance, resulting in a decrease in Nav1.5 expression. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1756-2651 |
| Relation: | https://doi.org/10.1093/jb/mvab066; https://shiga-med.repo.nii.ac.jp/?action=repository_uri&item_id=4105; http://hdl.handle.net/10422/00013199; Journal of biochemistry, 170(5), 577-585(2021-12-28) |
| الاتاحة: | http://hdl.handle.net/10422/00013199 https://shiga-med.repo.nii.ac.jp/?action=repository_uri&item_id=4105 |
| Rights: | ©The Author(s) 2021. ; Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved |
| رقم الانضمام: | edsbas.5DA8864B |
| قاعدة البيانات: | BASE |
| تدمد: | 17562651 |
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