The E3 ubiquitin ligase HectD3 attenuates cardiac hypertrophy and inflammation in mice

Commun Biol. 2020 Oct 9;3(1):562. doi: 10.1038/s42003-020-01289-2.


Myocardial inflammation has recently been recognized as a distinct feature of cardiac hypertrophy and heart failure. HectD3, a HECT domain containing E3 ubiquitin ligase has previously been investigated in the host defense against infections as well as neuroinflammation; its cardiac function however is still unknown. Here we show that HectD3 simultaneously attenuates Calcineurin-NFAT driven cardiomyocyte hypertrophy and the pro-inflammatory actions of LPS/interferon-γ via its cardiac substrates SUMO2 and Stat1, respectively. AAV9-mediated overexpression of HectD3 in mice in vivo not only reduced cardiac SUMO2/Stat1 levels and pathological hypertrophy but also largely abolished macrophage infiltration and fibrosis induced by pressure overload. Taken together, we describe a novel cardioprotective mechanism involving the ubiquitin ligase HectD3, which links anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and Stat1. In a broader perspective, these findings support the notion that cardiomyocyte growth and inflammation are more intertwined than previously anticipated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Cardiomegaly / enzymology
  • Cardiomegaly / metabolism*
  • Cardiomegaly / prevention & control
  • Humans
  • Immunoprecipitation
  • Mice
  • Microscopy, Fluorescence
  • Myocarditis / enzymology
  • Myocarditis / metabolism*
  • Myocarditis / prevention & control
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism
  • RAW 264.7 Cells
  • Rats
  • Rats, Wistar
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Sumoylation
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitin-Protein Ligases / physiology


  • STAT1 Transcription Factor
  • SUMO2 protein, mouse
  • Small Ubiquitin-Related Modifier Proteins
  • Stat1 protein, mouse
  • HECTd3 protein, mouse
  • Ubiquitin-Protein Ligases
  • Calcineurin