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

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. Brumell and Peter P. Liu ()
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Liyong Zhang: University of Ottawa Heart Institute
Xin Chen: University of Ottawa Heart Institute
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
Alex D. Sheftel: University of Ottawa Heart Institute
Fayez Dawood: University of Ottawa Heart Institute
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
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
Peter P. Liu: University of Ottawa Heart Institute

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4430

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