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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 P; Eriksson, Urs (2014). The adapter protein c-Cbl-associated protein (CAP) protects from acute CVB3-mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity. Basic Research in Cardiology, 109(3):411.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Physiology (medical), Physiology, Cardiology and Cardiovascular Medicine
Language:English
Date:1 May 2014
Deposited On:23 Jul 2019 14:46
Last Modified:25 Sep 2019 00:38
Publisher:Springer
ISSN:0300-8428
OA Status:Green
Publisher DOI:https://doi.org/10.1007/s00395-014-0411-3
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicencespringer101007s0039501404113 (Library Catalogue)

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