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

Yan-Xiao Ji1,2,3, Peng Zhang1,2,3, Xiao-Jing Zhang1,2,3

  • 1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.

Nature Communications
|June 2, 2016
PubMed

Insights

Tumour necrosis factor receptor-associated factor 6 (TRAF6) acts as a molecular switch in cardiac hypertrophy. Increased TRAF6, regulated by reactive oxygen species (ROS), exacerbates heart enlargement, while its deficiency alleviates it.

Area of Science:

  • Cardiovascular Biology
  • Molecular Mechanisms of Disease
  • Signaling Pathways

Background:

  • Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a key ubiquitin E3 ligase involved in various biological processes.
  • The specific role of TRAF6 in the development of cardiac hypertrophy has not been previously elucidated.

Purpose of the Study:

  • To investigate the role of TRAF6 in cardiac hypertrophy.
  • To elucidate the underlying molecular mechanisms by which TRAF6 influences cardiac remodeling.

Main Methods:

  • Analysis of TRAF6 expression in human and murine hypertrophied hearts.
  • Utilizing cardiac-specific Traf6 overexpression and deficiency mouse models under pressure overload and Angiotensin II (Ang II) challenge.
  • Investigating the interaction between TRAF6, reactive oxygen species (ROS), TAB2, and transforming growth factor beta-activated kinase 1 (TAK1).

Main Results:

  • TRAF6 levels are elevated in hypertrophied hearts and are regulated by ROS production.
  • Cardiac-specific TRAF6 overexpression worsens cardiac hypertrophy, whereas Traf6 deficiency ameliorates the hypertrophic phenotype.
  • ROS triggers TRAF6 auto-ubiquitination, facilitating TAK1 binding and activation, which is crucial for TRAF6-mediated cardiac remodeling.

Conclusions:

  • TRAF6 is upregulated in cardiac hypertrophy, driven by ROS.
  • TRAF6 acts as a critical molecular switch, promoting cardiac hypertrophy through TAK1 activation in a ROS-dependent manner.

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