RGD Reference Report - The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling. - Rat Genome Database

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The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling.

Authors: Ji, Yan-Xiao  Zhang, Peng  Zhang, Xiao-Jing  Zhao, Yi-Chao  Deng, Ke-Qiong  Jiang, Xi  Wang, Pi-Xiao  Huang, Zan  Li, Hongliang 
Citation: Ji YX, etal., Nat Commun. 2016 Jun 1;7:11267. doi: 10.1038/ncomms11267.
RGD ID: 155646134
Pubmed: PMID:27249171   (View Abstract at PubMed)
PMCID: PMC4895385   (View Article at PubMed Central)
DOI: DOI:10.1038/ncomms11267   (Journal Full-text)

Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a ubiquitin E3 ligase that regulates important biological processes. However, the role of TRAF6 in cardiac hypertrophy remains unknown. Here, we show that TRAF6 levels are increased in human and murine hypertrophied hearts, which is regulated by reactive oxygen species (ROS) production. Cardiac-specific Traf6 overexpression exacerbates cardiac hypertrophy in response to pressure overload or angiotensin II (Ang II) challenge, whereas Traf6 deficiency causes an alleviated hypertrophic phenotype in mice. Mechanistically, we show that ROS, generated during hypertrophic progression, triggers TRAF6 auto-ubiquitination that facilitates recruitment of TAB2 and its binding to transforming growth factor beta-activated kinase 1 (TAK1), which, in turn, enables the direct TRAF6-TAK1 interaction and promotes TAK1 ubiquitination. The binding of TRAF6 to TAK1 and the induction of TAK1 ubiquitination and activation are indispensable for TRAF6-regulated cardiac remodelling. Taken together, we define TRAF6 as an essential molecular switch leading to cardiac hypertrophy in a TAK1-dependent manner.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MAP3K7Humandilated cardiomyopathy  IEP protein:increased phosphorylation:heart (human)RGD 
Map3k7Mousedilated cardiomyopathy  ISOMAP3K7 (Homo sapiens)protein:increased phosphorylation:heart (human)RGD 
Map3k7Ratdilated cardiomyopathy  ISOMAP3K7 (Homo sapiens)protein:increased phosphorylation:heart (human)RGD 
MAP3K7Humanhypertrophic cardiomyopathy treatmentISOMap3k7 (Mus musculus) RGD 
MAP3K7Humanhypertrophic cardiomyopathy  IEP protein:increased phosphorylation:heart (human)RGD 
MYH7Humanhypertrophic cardiomyopathy treatmentISOMyh7 (Mus musculus)protein:increased expression:heart (human)RGD 
Map3k7Rathypertrophic cardiomyopathy treatmentISOMap3k7 (Mus musculus) RGD 
Map3k7Mousehypertrophic cardiomyopathy  ISOMAP3K7 (Homo sapiens)protein:increased phosphorylation:heart (human)RGD 
Map3k7Mousehypertrophic cardiomyopathy treatmentIMP  RGD 
Map3k7Rathypertrophic cardiomyopathy  ISOMAP3K7 (Homo sapiens)protein:increased phosphorylation:heart (human)RGD 
Myh7Mousehypertrophic cardiomyopathy treatmentIEP protein:increased expression:heart (human)RGD 
Myh7Rathypertrophic cardiomyopathy treatmentISOMyh7 (Mus musculus)protein:increased expression:heart (human)RGD 
NPPAHumanhypertrophic cardiomyopathy treatmentISONppa (Mus musculus)protein:increased expression:heart (human)RGD 
NppaRathypertrophic cardiomyopathy treatmentISONppa (Mus musculus)protein:increased expression:heart (human)RGD 
NppaMousehypertrophic cardiomyopathy treatmentIEP protein:increased expression:heart (human)RGD 
TRAF6Humanhypertrophic cardiomyopathy treatmentISOTraf6 (Mus musculus)protein:increased expression:heart (human)RGD 
Traf6Rathypertrophic cardiomyopathy treatmentISOTraf6 (Mus musculus)protein:increased expression:heart (human)RGD 
Traf6Mousehypertrophic cardiomyopathy treatmentIEP protein:increased expression:heart (human)RGD 
Traf6Mousehypertrophic cardiomyopathy treatmentIMP  RGD 
MYH7Humanintrinsic cardiomyopathy  IEP protein:increased expression:heart (human)RGD 
Myh7Ratintrinsic cardiomyopathy  ISOMYH7 (Homo sapiens)protein:increased expression:heart (human)RGD 
Myh7Mouseintrinsic cardiomyopathy  ISOMYH7 (Homo sapiens)protein:increased expression:heart (human)RGD 
NPPAHumanintrinsic cardiomyopathy  IEP protein:increased expression:heart (human)RGD 
NppaRatintrinsic cardiomyopathy  ISONPPA (Homo sapiens)protein:increased expression:heart (human)RGD 
NppaMouseintrinsic cardiomyopathy  ISONPPA (Homo sapiens)protein:increased expression:heart (human)RGD 
TRAF6Humanintrinsic cardiomyopathy  IEP protein:increased expression:heart (human)RGD 
Traf6Ratintrinsic cardiomyopathy  ISOTRAF6 (Homo sapiens)protein:increased expression:heart (human)RGD 
Traf6Mouseintrinsic cardiomyopathy  ISOTRAF6 (Homo sapiens)protein:increased expression:heart (human)RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TRAF6Humanangiotensin II increases expression ISOTraf6 (Rattus norvegicus)Angiotensin II increases expression of Traf6 protein in rat neonatal cardiomyocytesRGD 
Traf6Ratangiotensin II increases expression EXP Angiotensin II increases expression of Traf6 protein in rat neonatal cardiomyocytesRGD 
Traf6Mouseangiotensin II increases expression ISOTraf6 (Rattus norvegicus)Angiotensin II increases expression of Traf6 protein in rat neonatal cardiomyocytesRGD 
TRAF6Humanapocynin multiple interactionsISOTraf6 (Rattus norvegicus)Apocynin inhibits the reaction [hydrogen peroxide increases expression of Traf6 protein in rat neonatal cardiomyocytes]RGD 
Traf6Ratapocynin multiple interactionsEXP Apocynin inhibits the reaction [hydrogen peroxide increases expression of Traf6 protein in rat neonatal cardiomyocytes]RGD 
Traf6Mouseapocynin multiple interactionsISOTraf6 (Rattus norvegicus)Apocynin inhibits the reaction [hydrogen peroxide increases expression of Traf6 protein in rat neonatal cardiomyocytes]RGD 
TRAF6Humanhydrogen peroxide increases expression ISOTraf6 (Rattus norvegicus)Hydrogen peroxide increases expression of Traf6 protein in rat neonatal cardiomyocytesRGD 
TRAF6Humanhydrogen peroxide multiple interactionsISOTraf6 (Rattus norvegicus)N-acetyl-L-cysteine inhibits the reaction [hydrogen peroxide increases expression of Traf6 protein in rat neonatal cardiomyocytes]RGD 
Traf6Rathydrogen peroxide increases expression EXP Hydrogen peroxide increases expression of Traf6 protein in rat neonatal cardiomyocytesRGD 
Traf6Rathydrogen peroxide multiple interactionsEXP N-acetyl-L-cysteine inhibits the reaction [hydrogen peroxide increases expression of Traf6 protein in rat neonatal cardiomyocytes]RGD 
Traf6Mousehydrogen peroxide increases expression ISOTraf6 (Rattus norvegicus)Hydrogen peroxide increases expression of Traf6 protein in rat neonatal cardiomyocytesRGD 
Traf6Mousehydrogen peroxide multiple interactionsISOTraf6 (Rattus norvegicus)N-acetyl-L-cysteine inhibits the reaction [hydrogen peroxide increases expression of Traf6 protein in rat neonatal cardiomyocytes]RGD 
TAB2HumanN-acetyl-L-cysteine decreases bindingISOTab2 (Rattus norvegicus)N-acetyl-cysteine inhibits binding of Traf6 protein to Tab2 in rat neonatal cardiomyocytesRGD 
TRAF6HumanN-acetyl-L-cysteine multiple interactionsISOTraf6 (Rattus norvegicus)N-acetyl-L-cysteine inhibits the reaction [angiotensin II increases expression of Traf6 protein in rat neonatal cardiomyocytes]RGD 
TRAF6HumanN-acetyl-L-cysteine decreases bindingISOTraf6 (Rattus norvegicus)N-acetyl-cysteine inhibits binding of Traf6 protein to Tab2 in rat neonatal cardiomyocytesRGD 
Tab2RatN-acetyl-L-cysteine decreases bindingEXP N-acetyl-cysteine inhibits binding of Traf6 protein to Tab2 in rat neonatal cardiomyocytesRGD 
Tab2MouseN-acetyl-L-cysteine decreases bindingISOTab2 (Rattus norvegicus)N-acetyl-cysteine inhibits binding of Traf6 protein to Tab2 in rat neonatal cardiomyocytesRGD 
Traf6RatN-acetyl-L-cysteine decreases bindingEXP N-acetyl-cysteine inhibits binding of Traf6 protein to Tab2 in rat neonatal cardiomyocytesRGD 
Traf6RatN-acetyl-L-cysteine multiple interactionsEXP N-acetyl-L-cysteine inhibits the reaction [angiotensin II increases expression of Traf6 protein in rat neonatal cardiomyocytes]RGD 
Traf6MouseN-acetyl-L-cysteine decreases bindingISOTraf6 (Rattus norvegicus)N-acetyl-cysteine inhibits binding of Traf6 protein to Tab2 in rat neonatal cardiomyocytesRGD 
Traf6MouseN-acetyl-L-cysteine multiple interactionsISOTraf6 (Rattus norvegicus)N-acetyl-L-cysteine inhibits the reaction [angiotensin II increases expression of Traf6 protein in rat neonatal cardiomyocytes]RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  

Objects Annotated

Genes (Rattus norvegicus)
Map3k7  (mitogen activated protein kinase kinase kinase 7)
Myh7  (myosin heavy chain 7)
Nppa  (natriuretic peptide A)
Tab2  (TGF-beta activated kinase 1/MAP3K7 binding protein 2)
Traf6  (TNF receptor associated factor 6)

Genes (Mus musculus)
Map3k7  (mitogen-activated protein kinase kinase kinase 7)
Myh7  (myosin, heavy polypeptide 7, cardiac muscle, beta)
Nppa  (natriuretic peptide type A)
Tab2  (TGF-beta activated kinase 1/MAP3K7 binding protein 2)
Traf6  (TNF receptor-associated factor 6)

Genes (Homo sapiens)
MAP3K7  (mitogen-activated protein kinase kinase kinase 7)
MYH7  (myosin heavy chain 7)
NPPA  (natriuretic peptide A)
TAB2  (TGF-beta activated kinase 1 (MAP3K7) binding protein 2)
TRAF6  (TNF receptor associated factor 6)


Additional Information