RGD Reference Report - RNF207 exacerbates pathological cardiac hypertrophy via post-translational modification of TAB1. - Rat Genome Database

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RNF207 exacerbates pathological cardiac hypertrophy via post-translational modification of TAB1.

Authors: Yuan, Lin  Bu, Shichen  Du, Meng  Wang, Yilong  Ju, Chenhui  Huang, Dandan  Xu, Wenjing  Tan, Xin  Liang, Minglu  Deng, Shan  Yang, Liu  Huang, Kai 
Citation: Yuan L, etal., Cardiovasc Res. 2022 Mar 30:cvac039. doi: 10.1093/cvr/cvac039.
RGD ID: 155804287
Pubmed: PMID:35352799   (View Abstract at PubMed)
DOI: DOI:10.1093/cvr/cvac039   (Journal Full-text)


AIMS: The heart undergoes pathological remodeling, featured by the hypertrophic growth of cardiomyocytes and increased cardiac fibrosis, under biomechanical stress such as hemodynamic overload. RNF207 is an E3 ubiquitin ligase that is predominantly expressed in the heart, but its function remains elusive. In this study, we aimed to explore the role of RNF207 in the development of pathological cardiac hypertrophy and dysfunction.
METHODS AND RESULTS: Transverse aortic constriction (TAC) surgery was performed on mice to induce cardiac hypertrophy. Cardiac function and remodeling were evaluated by echocardiography, histological assessment and molecular analyses. Our data indicated that RNF207 overexpression (OE) exacerbated cardiac hypertrophy, fibrosis and systolic dysfunction. In contrast, TAC-induced cardiac remodeling was profoundly blunted in RNF207 knockdown (KD) hearts. In line with the in vivo findings, RNF207 OE augmented, while RNF207 KD alleviated, phenylephrine-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we demonstrated that RNF207 elicited detrimental effects by promoting K63-linked ubiquitination of TAB1, which triggered the autophosphorylation of TAK1 and the activation of downstream p38 and JNK1/2 signaling pathways. In the TAB1 knockdown cardiomyocytes, RNF207 OE-induced cell hypertrophy was significantly attenuated, indicating that RNF207-induced hypertrophy is, at least in part, TAB1 dependent.
CONCLUSIONS: This study demonstrates that RNF207 exacerbates pressure overload-induced cardiac hypertrophy and dysfunction via post-translational modification of TAB1.
TRANSLATIONAL PERSPECTIVE: There is currently a lack of treatment to effectively prevent or reverse cardiac hypertrophy and heart failure, which has brought the importance of in-depth understanding of the molecular mechanisms that drives the pathological cardiac growth and the discovery of novel therapeutic targets. Our work demonstrates for the first time that RNF207 exaggerates pressure overload-induced cardiac hypertrophy and dysfunction. This is due, at least in part, to the polyubiquitination of TAB1, which triggers the autophosphorylation of TAK1 and activation of TAK1-p38 and TAK1-JNK1/2 signaling pathways. These data suggest that RNF207 may be a potential therapeutic target in the treatment of cardiac hypertrophy and failure.

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
phenylephrine multiple interactionsISOMap3k7 (Rattus norvegicus)155804287; 155804287Phenylephrine promotes the reaction [Map3k7 protein binds to Tab1 protein in neonatal cardiomyocytes]RGD 
phenylephrine multiple interactionsEXP 155804287Phenylephrine promotes the reaction [Map3k7 protein binds to Tab1 protein in neonatal cardiomyocytes]RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
MAP kinase kinase kinase activity  IPIMap3k7 (Rattus norvegicus)155804287 RGD 
protein binding  IPITab1 (Rattus norvegicus)155804287 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Map3k7  (mitogen activated protein kinase kinase kinase 7)
Tab1  (TGF-beta activated kinase 1/MAP3K7 binding protein 1)

Genes (Mus musculus)
Map3k7  (mitogen-activated protein kinase kinase kinase 7)

Genes (Homo sapiens)
MAP3K7  (mitogen-activated protein kinase kinase kinase 7)


Additional Information