c-FLIP-Short Reduces Type I Interferon Production and Increases Viremia with Coxsackievirus B3
Year: 2014
Type: article
Abstract: Cellular FLIP (c-FLIP) is an enzymatically inactive paralogue of caspase-8 and as such can block death receptor-induced apoptosis. However, independent of death receptors, c-FLIP-Long (c-FLIPL) can heterodimerize with and activate caspase-8. This is critical for promoting the growth and survival of T lymphocytes as well as the regulation of the RIG-I helicase pathway for type I interferon production in response to viral infections. Truncated forms of FLIP also exist in mammalian cells (c-FLIPS) and certain viruses (v-FLIP), which lack the C-terminal domain that activates caspase-8. Thus, the ratio of c-FLIPL to these short forms of FLIP may greatly influence the outcome of an immune response. We examined this model in mice transgenically expressing c-FLIPS in T cells during infection with Coxsackievirus B3 (CVB3). In contrast to our earlier findings of reduced myocarditis and mortality with CVB3 infection of c-FLIPL-transgenic mice, c-FLIPS-transgenic mice were highly sensitive to CVB3 infection as manifested by increased cardiac virus titers, myocarditis score, and mortality compared to wild-type C57BL/6 mice. This observation was paralleled by a reduction in serum levels of IL-10 and IFN-α in CVB3-infected c-FLIPS mice. In vitro infection of c-FLIPS T cells with CVB3 confirmed these results. Furthermore, molecular studies revealed that following infection of cells with CVB3, c-FLIPL associates with mitochondrial antiviral signaling protein (MAVS), increases caspase-8 activity and type I IFN production, and reduces viral replication, whereas c-FLIPS promotes the opposite phenotype.
Source: PLoS ONE
Authors: Iwona A. Buskiewicz, Andreas Koenig, Brian Roberts, Jennifer Russell, Cuixia Shi, Sun-Hwa Lee, Jae U. Jung, Sally A. Huber, Ralph C. Budd
Institutions: University of Vermont, University of Southern California
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: Fletcher Jones Foundation, Hastings Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Dental and Craniofacial Research
Awards: G1047356652, G1156522830, T reg Cells in Myocarditis, G1419934659, G1850526206, G1884091991, G2164813847, G292170998, G3027522735, G3537039052, G3601330622, G391342467, G3963602007, G406480652, G4117621356, G538359489, G5515774457, G5641079710, G638221479, G6989976097, G7804559710, G8549599477, G8768997755, G9000017072, G9000031411, G9000120934, G9000143538, G9000154338, G9000248713, G9000273975, G9000284507, G9000332358, G986974877
OpenAlex ID: W2024905131