Foot-and-Mouth Disease Virus 3C Protease Cleaves NEMO To Impair Innate Immune Signaling
- 1 September 2012
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 86 (17), 9311-9322
- https://doi.org/10.1128/jvi.00722-12
Abstract
Foot-and-mouth disease is a highly contagious viral illness of wild and domestic cloven-hoofed animals. The causative agent, foot-and-mouth disease virus (FMDV), replicates rapidly, efficiently disseminating within the infected host and being passed on to susceptible animals via direct contact or the aerosol route. To survive in the host, FMDV has evolved to block the host interferon (IFN) response. Previously, we and others demonstrated that the leader proteinase (L pro ) of FMDV is an IFN antagonist. Here, we report that another FMDV-encoded proteinase, 3C pro , also inhibits IFN-α/β response and the expression of IFN-stimulated genes. Acting in a proteasome- and caspase-independent manner, the 3C pro of FMDV proteolytically cleaved nuclear transcription factor kappa B (NF-κB) essential modulator (NEMO), a bridging adaptor protein essential for activating both NF-κB and interferon-regulatory factor signaling pathways. 3C pro specifically targeted NEMO at the Gln 383 residue, cleaving off the C-terminal zinc finger domain from the protein. This cleavage impaired the ability of NEMO to activate downstream IFN production and to act as a signaling adaptor of the RIG-I/MDA5 pathway. Mutations specifically disrupting the cysteine protease activity of 3C pro abrogated NEMO cleavage and the inhibition of IFN induction. Collectively, our data identify NEMO as a substrate for FMDV 3C pro and reveal a novel mechanism evolved by a picornavirus to counteract innate immune signaling.Keywords
This publication has 62 references indexed in Scilit:
- A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKγ to dampen the host NF-κB-mediated inflammatory responseNature, 2009
- RIG-I is cleaved during picornavirus infectionVirology, 2009
- Ubiquitination and proteasomal degradation of interferon regulatory factor-3 induced by Npro from a cytopathic bovine viral diarrhea virusVirology, 2007
- The NEMO adaptor bridges the nuclear factor-κB and interferon regulatory factor signaling pathwaysNature Immunology, 2007
- Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursorProceedings of the National Academy of Sciences of the United States of America, 2007
- Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirusProceedings of the National Academy of Sciences of the United States of America, 2006
- Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virusNature, 2005
- Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3Cell, 2005
- VISA Is an Adapter Protein Required for Virus-Triggered IFN-β SignalingMolecular Cell, 2005
- IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon inductionNature Immunology, 2005