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The adapter protein c-Cbl-associated protein (CAP) protects from acute CVB3-mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity

Valaperti, Alan ; Nishii, Mototsugu ; Liu, Youan ; Yang, Howard ; Naito, Kotaro ; Liu, Peter ; Eriksson, Urs

In: Basic Research in Cardiology, 2014, vol. 109, no. 3, p. 1-14

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    Titre
    • The adapter protein c-Cbl-associated protein (CAP) protects from acute CVB3-mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity
    Auteur
    • Valaperti, Alan. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
    • Nishii, Mototsugu. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
    • Liu, Youan. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
    • Yang, Howard. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
    • Naito, Kotaro. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
    • Liu, Peter. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
    • Eriksson, Urs. Division of Cardioimmunology, Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Basic Research in Cardiology, 2014, vol. 109, no. 3, p. 1-14. Springer Berlin Heidelberg
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:325985
    Summary
    c-Cbl-associated protein (CAP), also called Sorbs1 or ponsin, has been described as an essential adapter protein in the insulin-signalling pathway. Here, we describe for the first time a unique protective role for CAP in viral myocarditis. Mortality and heart failure development were increased in CAP−/− mice compared to CAP+/+ littermates after Coxsackievirus (CVB3) infection. Mechanistically, CAP protected from tissue apoptosis because of reduced CD8+ T and natural killer cell cytotoxicity. Despite reduced cytotoxic elimination of CVB3-infected cells in CAP+/+ hearts, however, CAP enhanced interferon regulatory factor 3(IRF3)-dependent antiviral type I interferon production and decreased viral proliferation in vitro by binding to the cytoplasmic RIG-I-like receptor melanoma differentiation-associated protein 5 (MDA5). Taken together, these findings reveal a novel modulatory role for CAP in the heart as a key protein stabilizing antiviral type I interferon production, while protecting from excessive cytotoxic responses. Our study will help to define future strategies to develop treatments to limit detrimental responses during viral heart inflammation.