ASB2 is a novel E3 ligase of SMAD9 required for cardiogenesis.
Animals
Humans
Mice
Bone Morphogenetic Proteins
/ metabolism
Cell Differentiation
Gene Expression Profiling
Gene Expression Regulation, Developmental
Heart
/ embryology
HEK293 Cells
Oligonucleotide Array Sequence Analysis
Proteasome Endopeptidase Complex
/ metabolism
Signal Transduction
Smad8 Protein
/ biosynthesis
Suppressor of Cytokine Signaling Proteins
/ biosynthesis
Ubiquitin
/ chemistry
Ubiquitin-Protein Ligases
/ metabolism
Zebrafish
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
29 11 2021
29 11 2021
Historique:
received:
15
06
2021
accepted:
15
11
2021
entrez:
30
11
2021
pubmed:
1
12
2021
medline:
15
2
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34845242
doi: 10.1038/s41598-021-02390-0
pii: 10.1038/s41598-021-02390-0
pmc: PMC8630118
doi:
Substances chimiques
Asb2 protein, mouse
0
ASB2 ubiqutin ligase, zebrafish
0
Bone Morphogenetic Proteins
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
Smad8 Protein
0
Smad9 protein, mouse
0
Suppressor of Cytokine Signaling Proteins
0
Ubiquitin
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
SMAD9 protein, zebrafish
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
23056Informations de copyright
© 2021. The Author(s).
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