title: iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death.
abstract: Desmosomes are anchoring junctions that exist in cells that endure physical stress such as cardiac myocytes. The importance of desmosomes in maintaining the homeostasis of the myocardium is underscored by frequent mutations of desmosome components found in human patients and animal models. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a phenotype caused by mutations in desmosomal components in ∼ 50% of patients, however, the causes in the remaining 50% of patients still remain unknown. A deficiency of inhibitor of apoptosis-stimulating protein of p53 (iASPP), an evolutionarily conserved inhibitor of p53, caused by spontaneous mutation recently has been associated with a lethal autosomal recessive cardiomyopathy in Poll Hereford calves and Wa3 mice. However, the molecular mechanisms that mediate this putative function of iASPP are completely unknown. Here, we show that iASPP is expressed at intercalated discs in human and mouse postmitotic cardiomyocytes. iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks in vitro and in vivo. iASPP deficiency specifically induces right ventricular dilatation in mouse embryos at embryonic day 16.5. iASPP-deficient mice with exon 8 deletion (Ppp1r13l(Δ8/Δ8)) die of sudden cardiac death, displaying features of ARVC. Intercalated discs in cardiomyocytes from four of six human ARVC cases show reduced or loss of iASPP. ARVC-derived desmoplakin mutants DSP-1-V30M and DSP-1-S299R exhibit weaker binding to iASPP. These data demonstrate that by interacting with desmoplakin and desmin, iASPP is an important regulator of desmosomal function both in vitro and in vivo. This newly identified property of iASPP may provide new molecular insight into the pathogenesis of ARVC.
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
authors.forename: Mario
authors.initials: M
authors.lastname: Notari
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
authors.forename: Gopinath
authors.initials: G
authors.lastname: Sutendra
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Dedeić
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Developmental Biology Division, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: Laurent
authors.initials: L
authors.lastname: Dupays
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Arash
authors.initials: A
authors.lastname: Yavari
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Carr
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Medicine, University College London, London WC1E 6JJ, United Kingdom;
authors.forename: Aaisha
authors.initials: A
authors.lastname: Opel
authors.affiliation: Department of Medicine, University College London, London WC1E 6JJ, United Kingdom;
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.affiliation: Nuffield Department of Clinical Laboratory Science, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom;
authors.forename: David J P
authors.initials: DJ
authors.lastname: Ferguson
authors.affiliation: Centre for Cutaneous Research, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom;
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
authors.affiliation: Centre for Cardiovascular Risk in Younger Persons, Department of Cardiovascular Pathology, Cardiovascular Sciences Research Centre, St. George's University of London, London SW17 0RE, United Kingdom; and.
authors.forename: Sofia
authors.initials: S
authors.lastname: de Noronha
authors.affiliation: Centre for Cardiovascular Risk in Younger Persons, Department of Cardiovascular Pathology, Cardiovascular Sciences Research Centre, St. George's University of London, London SW17 0RE, United Kingdom; and.
authors.forename: Mary N
authors.initials: MN
authors.lastname: Sheppard
authors.affiliation: Section of Virology, Faculty of Medicine, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Hollinshead
authors.affiliation: Developmental Biology Division, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom;
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mohun
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom; Xin.Lu@ludwig.ox.ac.uk.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002461:Cell Line, Transformed; D003645:Death, Sudden; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism; D003896:Desmosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007382:Intermediate Filaments; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D003893:Desmin; D051180:Desmoplakins; D047908:Intracellular Signaling Peptides and Proteins; C119612:PPP1R13L protein, human; D012097:Repressor Proteins
keywords: ARVC; cell–cell junctions; desmosome; iASPP; sudden death