RRC ID 69910
Author Min KD, Asakura M, Shirai M, Yamazaki S, Ito S, Fu HY, Asanuma H, Asano Y, Minamino T, Takashima S, Kitakaze M.
Title ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis.
Journal Sci Rep
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.
Volume 11(1)
Pages 23056
Published 2021-11-29
DOI 10.1038/s41598-021-02390-0
PII 10.1038/s41598-021-02390-0
PMID 34845242
PMC PMC8630118
MeSH Animals Bone Morphogenetic Proteins / metabolism Cell Differentiation Gene Expression Profiling Gene Expression Regulation, Developmental HEK293 Cells Heart* / embryology Humans Mice Oligonucleotide Array Sequence Analysis Proteasome Endopeptidase Complex / metabolism Signal Transduction Smad8 Protein* / biosynthesis Smad8 Protein* / physiology Suppressor of Cytokine Signaling Proteins* / biosynthesis Suppressor of Cytokine Signaling Proteins* / physiology Ubiquitin / chemistry Ubiquitin / physiology Ubiquitin-Protein Ligases / metabolism Zebrafish
IF 3.998
Human and Animal Cells P19.CL6(RCB2318)