title: HACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress.
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.
authors.affiliation: 1] 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.
authors.forename: Liyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 1] 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Parveen
authors.initials: P
authors.lastname: Sharma
authors.affiliation: 1] 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.
authors.forename: Mark
authors.initials: M
authors.lastname: Moon
authors.affiliation: University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7.
authors.forename: Alex D
authors.initials: AD
authors.lastname: Sheftel
authors.affiliation: 1] 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.
authors.forename: Fayez
authors.initials: F
authors.lastname: Dawood
authors.affiliation: 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.
authors.forename: Mai P
authors.initials: MP
authors.lastname: Nghiem
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.affiliation: 1] 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.
authors.forename: Anthony O
authors.initials: AO
authors.lastname: Gramolini
authors.affiliation: Department of Molecular Oncology, BC Cancer Research Center, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr Bohrgasse 3, A-1030 Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: 1] 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.
authors.forename: John H
authors.initials: JH
authors.lastname: Brumell
authors.affiliation: 1] 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.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000235:genetics; D002478:Cells, Cultured; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics / Q000502:physiology*; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D059748:Proteolysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071456:Sequestosome-1 Protein; D013312:Stress, Physiological / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D016474:Weight-Bearing / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025521:Tumor Suppressor Proteins; C000591483:HACE1 protein, mouse; D044767:Ubiquitin-Protein Ligases