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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    • "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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