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

Author

Listed:
  • Liyong Zhang

    (University of Ottawa Heart Institute
    Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network)

  • Xin Chen

    (University of Ottawa Heart Institute
    Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network)

  • Parveen Sharma

    (Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network)

  • Mark Moon

    (University of Ottawa Heart Institute
    Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network)

  • Alex D. Sheftel

    (University of Ottawa Heart Institute)

  • Fayez Dawood

    (University of Ottawa Heart Institute
    Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network)

  • Mai P. Nghiem

    (Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network)

  • Jun Wu

    (Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network)

  • Ren-Ke Li

    (Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network)

  • Anthony O. Gramolini

    (Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network
    University of Toronto)

  • Poul H. Sorensen

    (BC Cancer Research Center, University of British Columbia)

  • Josef M. Penninger

    (Institute of Molecular Biotechnology of the Austrian Academy of Sciences)

  • John H. Brumell

    (University of Toronto
    Institute of Medical Science, University of Toronto
    Cell Biology Program, Hospital for Sick Children)

  • Peter P. Liu

    (University of Ottawa Heart Institute
    Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network
    University of Toronto
    Institute of Medical Science, University of Toronto)

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.

Suggested Citation

  • Liyong Zhang & Xin Chen & Parveen Sharma & Mark Moon & Alex D. Sheftel & Fayez Dawood & Mai P. Nghiem & Jun Wu & Ren-Ke Li & Anthony O. Gramolini & Poul H. Sorensen & Josef M. Penninger & John H. Brum, 2014. "HACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress," Nature Communications, Nature, vol. 5(1), pages 1-14, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4430
    DOI: 10.1038/ncomms4430
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