ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis

Abstract Cardiogenesis requires the orchestrated spatiotemporal tuning of BMP signalling upon the balance between induction and counter-acting suppression of the differentiation of the cardiac tissue. SMADs are key intracellular transducers and the selective degradation of SMADs by the ubiquitin–pro...

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Main Authors: Kyung-Duk Min, Masanori Asakura, Manabu Shirai, Satoru Yamazaki, Shin Ito, Hai Ying Fu, Hiroshi Asanuma, Yoshihiro Asano, Tetsuo Minamino, Seiji Takashima, Masafumi Kitakaze
Format: Article
Language:English
Published: Nature Portfolio 2021-11-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-021-02390-0
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author Kyung-Duk Min
Masanori Asakura
Manabu Shirai
Satoru Yamazaki
Shin Ito
Hai Ying Fu
Hiroshi Asanuma
Yoshihiro Asano
Tetsuo Minamino
Seiji Takashima
Masafumi Kitakaze
author_facet Kyung-Duk Min
Masanori Asakura
Manabu Shirai
Satoru Yamazaki
Shin Ito
Hai Ying Fu
Hiroshi Asanuma
Yoshihiro Asano
Tetsuo Minamino
Seiji Takashima
Masafumi Kitakaze
author_sort Kyung-Duk Min
collection DOAJ
description Abstract Cardiogenesis requires the orchestrated spatiotemporal tuning of BMP signalling upon the balance between induction and counter-acting suppression of the differentiation of the cardiac tissue. SMADs are key intracellular transducers and the selective degradation of SMADs by the ubiquitin–proteasome system is pivotal in the spatiotemporal tuning of BMP signalling. However, among three SMADs for BMP signalling, SMAD1/5/9, only the specific E3 ligase of SMAD9 remains poorly investigated. Here, we report for the first time that SMAD9, but not the other SMADs, is ubiquitylated by the E3 ligase ASB2 and targeted for proteasomal degradation. ASB2, as well as Smad9, is conserved among vertebrates. ASB2 expression was specific to the cardiac region from the very early stage of cardiac differentiation in embryogenesis of mouse. Knockdown of Asb2 in zebrafish resulted in a thinned ventricular wall and dilated ventricle, which were rescued by simultaneous knockdown of Smad9. Abundant Smad9 protein leads to dysregulated cardiac differentiation through a mechanism involving Tbx2, and the BMP signal conducted by Smad9 was downregulated under quantitative suppression of Smad9 by Asb2. Our findings demonstrate that ASB2 is the E3 ligase of SMAD9 and plays a pivotal role in cardiogenesis through regulating BMP signalling.
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spelling doaj.art-2198c64f663f4df99340febaa636532e2022-12-21T19:10:32ZengNature PortfolioScientific Reports2045-23222021-11-0111111510.1038/s41598-021-02390-0ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesisKyung-Duk Min0Masanori Asakura1Manabu Shirai2Satoru Yamazaki3Shin Ito4Hai Ying Fu5Hiroshi Asanuma6Yoshihiro Asano7Tetsuo Minamino8Seiji Takashima9Masafumi Kitakaze10Department of Clinical Research and Development, National Cerebral and Cardiovascular CenterDepartment of Clinical Research and Development, National Cerebral and Cardiovascular CenterDepartment of Bioscience, National Cerebral and Cardiovascular CenterDepartment of Cell Biology, National Cerebral and Cardiovascular CenterDepartment of Clinical Research and Development, National Cerebral and Cardiovascular CenterDepartment of Clinical Research and Development, National Cerebral and Cardiovascular CenterDepartment of Internal Medicine, Meiji University of Integrative MedicineDepartment of Cardiovascular Medicine, Osaka University Graduate School of MedicineDepartment of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa UniversityDepartment of Medical Biochemistry, Osaka University Graduate School of MedicineDepartment of Clinical Research and Development, National Cerebral and Cardiovascular CenterAbstract Cardiogenesis requires the orchestrated spatiotemporal tuning of BMP signalling upon the balance between induction and counter-acting suppression of the differentiation of the cardiac tissue. SMADs are key intracellular transducers and the selective degradation of SMADs by the ubiquitin–proteasome system is pivotal in the spatiotemporal tuning of BMP signalling. However, among three SMADs for BMP signalling, SMAD1/5/9, only the specific E3 ligase of SMAD9 remains poorly investigated. Here, we report for the first time that SMAD9, but not the other SMADs, is ubiquitylated by the E3 ligase ASB2 and targeted for proteasomal degradation. ASB2, as well as Smad9, is conserved among vertebrates. ASB2 expression was specific to the cardiac region from the very early stage of cardiac differentiation in embryogenesis of mouse. Knockdown of Asb2 in zebrafish resulted in a thinned ventricular wall and dilated ventricle, which were rescued by simultaneous knockdown of Smad9. Abundant Smad9 protein leads to dysregulated cardiac differentiation through a mechanism involving Tbx2, and the BMP signal conducted by Smad9 was downregulated under quantitative suppression of Smad9 by Asb2. Our findings demonstrate that ASB2 is the E3 ligase of SMAD9 and plays a pivotal role in cardiogenesis through regulating BMP signalling.https://doi.org/10.1038/s41598-021-02390-0
spellingShingle Kyung-Duk Min
Masanori Asakura
Manabu Shirai
Satoru Yamazaki
Shin Ito
Hai Ying Fu
Hiroshi Asanuma
Yoshihiro Asano
Tetsuo Minamino
Seiji Takashima
Masafumi Kitakaze
ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis
Scientific Reports
title ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis
title_full ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis
title_fullStr ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis
title_full_unstemmed ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis
title_short ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis
title_sort asb2 is a novel e3 ligase of smad9 required for cardiogenesis
url https://doi.org/10.1038/s41598-021-02390-0
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