The adapter protein c-Cbl-associated protein (CAP) protects from acute CVB3-mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity.
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.
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, alan.valaperti@vetbio.uzh.ch.
Alan
A
Valaperti
Mototsugu
M
Nishii
Youan
Y
Liu
Howard
H
Yang
Kotaro
K
Naito
Peter P
PP
Liu
Urs
U
Eriksson
D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D000072640:Interferon-Induced Helicase, IFIH1; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009205:Myocarditis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014779:Virus Replication
D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008840:Microfilament Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C119201:ponsin; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1