The Coxsackievirus B 3Cpro Protease Cleaves MAVS and TRIF to Attenuate Host Type I Interferon and Apoptotic Signaling

Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS Pathogens (Impact Factor: 7.56). 03/2011; 7(3):e1001311. DOI: 10.1371/journal.ppat.1001311
Source: PubMed


The host innate immune response to viral infections often involves the activation of parallel pattern recognition receptor (PRR) pathways that converge on the induction of type I interferons (IFNs). Several viruses have evolved sophisticated mechanisms to attenuate antiviral host signaling by directly interfering with the activation and/or downstream signaling events associated with PRR signal propagation. Here we show that the 3C(pro) cysteine protease of coxsackievirus B3 (CVB3) cleaves the innate immune adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1 receptor domain-containing adaptor inducing interferon-beta (TRIF) as a mechanism to escape host immunity. We found that MAVS and TRIF were cleaved in CVB3-infected cells in culture. CVB3-induced cleavage of MAVS and TRIF required the cysteine protease activity of 3C(pro), occurred at specific sites and within specialized domains of each molecule, and inhibited both the type I IFN and apoptotic signaling downstream of these adaptors. 3C(pro)-mediated MAVS cleavage occurred within its proline-rich region, led to its relocalization from the mitochondrial membrane, and ablated its downstream signaling. We further show that 3C(pro) cleaves both the N- and C-terminal domains of TRIF and localizes with TRIF to signalosome complexes within the cytoplasm. Taken together, these data show that CVB3 has evolved a mechanism to suppress host antiviral signal propagation by directly cleaving two key adaptor molecules associated with innate immune recognition.

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Available from: Amitava Mukherjee, Sep 23, 2015
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    • "CVB also can antagonize the apoptotic pathway in cells, allowing viral replication to proceed for a longer amount of time necessary to maximize progeny (Harris and Coyne, 2014). For example, CVB can cleave cell components of the pro-apoptotic family, including TRIF (Mukherjee et al., 2011), and viral 2B protein can act as viroporin disrupting Ca 2 þ gradients necessary to initiate apoptosis (Campanella et al., 2004). Evasion of the host antiviral response maximizes viral replication during acute infection and may also be critical for the establishment of viral persistence. "
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    ABSTRACT: Coxsackieviruses (CVs) are relatively common viruses associated with a number of serious human diseases, including myocarditis and meningo-encephalitis. These viruses are considered cytolytic yet can persist for extended periods of time within certain host tissues requiring evasion from the host immune response and a greatly reduced rate of replication. A member of Picornaviridae family, CVs have been historically considered non-enveloped viruses - although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection and the establishment of chronic disease in adults. CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 10/2015; 484. DOI:10.1016/j.virol.2015.06.006 · 3.32 Impact Factor
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    • "les assembly PV 3C ( White et al . , 2007 ) Sam68 Signal transduction and activation of RNA FMDV 3C ( Lawrence et al . , 2012 ) Nup62 , Nup98 , Nup153 Nuclear pore PV Rhino 2A ( Castello et al . , 2009 ; Park et al . , 2010 ; Watters and Palmenberg , 2011 ) RIG - 1 Antiviral response Barral et al . ( 2009 ) MAVS , TRIF Antiviral response CBV3 3C ( Mukherjee et al . , 2011 ) IRF7 Antiviral response FMDV 3C ( Du et al . , 2014 ) 80S ribosome with a Met - tRNA i in the P - site ready for translation elongation ( reviewed in Parsyan et al . , 2011 ) ."
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    Virus Research 01/2015; 206. DOI:10.1016/j.virusres.2015.01.012 · 2.32 Impact Factor
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    • "Our findings suggest that the various forms of FLIP confer either different substrate preferences for caspase-8 or possibly different locations within the cell, in association or not with RIP1. In this regard, the greater association of MAVS with c-FLIPL than with c-FLIPS during viral infection may profoundly affect not only the ability of RIG-I, FADD, and RIP1 to translocate to MAVS at the mitochondria, but c-FLIPL may also inhibit cleavage of MAVS by the CVB3 3Cpro protease [23]. Our findings thus offer an explanation why it would be preferable for viruses to acquire expression of the short form of FLIP rather than full-length FLIP. "
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    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.
    PLoS ONE 05/2014; 9(5):e96156. DOI:10.1371/journal.pone.0096156 · 3.23 Impact Factor
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