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Nat Commun. 2014 Mar 11;5:3430. doi: 10.1038/ncomms4430.

HACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress.

Author information

  • 11] University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7 [2] Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4.
  • 2Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4.
  • 3University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7.
  • 41] Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4 [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
  • 5Department of Molecular Oncology, BC Cancer Research Center, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1L3.
  • 6Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr Bohrgasse 3, A-1030 Vienna, Austria.
  • 71] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [2] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3] Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1 × 8.
  • 81] University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7 [2] Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4 [3] Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [4] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

Abstract

The HECT E3 ubiquitin ligase HACE1 is a tumour suppressor known to regulate Rac1 activity under stress conditions. HACE1 is increased in the serum of patients with heart failure. Here we show that HACE1 protects the heart under pressure stress by controlling protein degradation. Hace1 deficiency in mice results in accelerated heart failure and increased mortality under haemodynamic stress. Hearts from Hace1(-/-) mice display abnormal cardiac hypertrophy, left ventricular dysfunction, accumulation of LC3, p62 and ubiquitinated proteins enriched for cytoskeletal species, indicating impaired autophagy. Our data suggest that HACE1 mediates p62-dependent selective autophagic turnover of ubiquitinated proteins by its ankyrin repeat domain through protein-protein interaction, which is independent of its E3 ligase activity. This would classify HACE1 as a dual-function E3 ligase. Our finding that HACE1 has a protective function in the heart in response to haemodynamic stress suggests that HACE1 may be a potential diagnostic and therapeutic target for heart disease.

PMID:
24614889
[PubMed - in process]
PMCID:
PMC3959209
Free PMC Article

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