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The coxsackievirus B 3C<sup>pro</sup> protease cleaves MAVS and TRIF to attenuate host type I interferon and apoptotic signaling

Mukherjee, A and Morosky, SA and Delorme-Axford, E and Dybdahl-Sissoko, N and Oberste, MS and Wang, T and Coyne, CB (2011) The coxsackievirus B 3C<sup>pro</sup> protease cleaves MAVS and TRIF to attenuate host type I interferon and apoptotic signaling. PLoS Pathogens, 7 (3). ISSN 1553-7366

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Abstract

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 3Cpro 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 3Cpro, 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. 3Cpro-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 3Cpro 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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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Mukherjee, Aamm223@pitt.eduAMM223
Morosky, SAstm39@pitt.eduSTM39
Delorme-Axford, E
Dybdahl-Sissoko, N
Oberste, MS
Wang, T
Coyne, CB
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorHeise, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 March 2011
Date Type: Publication
Journal or Publication Title: PLoS Pathogens
Volume: 7
Number: 3
DOI or Unique Handle: 10.1371/journal.ppat.1001311
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
School of Medicine > Cell Biology and Molecular Physiology
School of Medicine > Microbiology and Molecular Genetics
Refereed: Yes
ISSN: 1553-7366
Date Deposited: 01 Jul 2014 16:13
Last Modified: 02 Feb 2019 16:56
URI: http://d-scholarship.pitt.edu/id/eprint/22123

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