Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / virology
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Cells, Cultured
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Coxsackievirus Infections / genetics
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Coxsackievirus Infections / immunology
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Coxsackievirus Infections / metabolism
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Coxsackievirus Infections / pathology
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Coxsackievirus Infections / prevention & control*
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Coxsackievirus Infections / virology
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DEAD-box RNA Helicases / metabolism
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Disease Models, Animal
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Enterovirus B, Human / genetics
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Enterovirus B, Human / growth & development
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Enterovirus B, Human / immunology*
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Enterovirus B, Human / pathogenicity
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Interferon Regulatory Factor-3 / metabolism
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Interferon Type I / metabolism*
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Interferon-Induced Helicase, IFIH1
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Killer Cells, Natural / virology
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Lymphocyte Activation
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microfilament Proteins / deficiency
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism*
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Myeloid Differentiation Factor 88 / metabolism
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Myocarditis / genetics
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Myocarditis / immunology
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Myocarditis / metabolism
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Myocarditis / pathology
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Myocarditis / prevention & control*
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Myocarditis / virology
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Myocardium / immunology
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Myocardium / metabolism*
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Myocardium / pathology
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Time Factors
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Virus Replication
Substances
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Interferon Regulatory Factor-3
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Interferon Type I
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Microfilament Proteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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ponsin
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Ifih1 protein, mouse
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DEAD-box RNA Helicases
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Interferon-Induced Helicase, IFIH1