Foot-and-mouth disease virus 3C protease cleaves NEMO to impair innate immune signaling

Dang Wang, Liurong Fang, Kui Li, Huijuan Zhong, Jinxiu Fan, Chao Ouyang, Huan Zhang, Erzhen Duan, Rui Luo, Zhongming Zhang, Xiangtao Liu, Huanchun Chen, Shaobo Xiao

Research output: Contribution to journalArticle

61 Citations (Scopus)

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 (Lpro) of FMDV is an IFN antagonist. Here, we report that another FMDV-encoded proteinase, 3Cpro, also inhibits IFN-α/β response and the expression of IFN-stimulated genes. Acting in a proteasome- and caspase-independent manner, the 3Cpro 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. 3Cpro 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 3Cpro abrogated NEMO cleavage and the inhibition of IFN induction. Collectively, our data identify NEMO as a substrate for FMDV 3Cpro and reveal a novel mechanism evolved by a picornavirus to counteract innate immune signaling.

Original languageEnglish (US)
Pages (from-to)9311-9322
Number of pages12
JournalJournal of Virology
Volume86
Issue number17
DOIs
StatePublished - Sep 1 2012

Fingerprint

Foot-and-mouth disease virus
Foot-and-Mouth Disease Virus
interferons
Interferons
proteinases
Interferon Regulatory Factors
Picornaviridae
Foot-and-Mouth Disease
transcription factor NF-kappa B
Cysteine Proteases
NF-kappa B
zinc finger motif
cysteine proteinases
caspases
Zinc Fingers
foot-and-mouth disease
proteasome endopeptidase complex
Proteasome Endopeptidase Complex
direct contact
Caspases

All Science Journal Classification (ASJC) codes

  • Immunology
  • Virology

Cite this

Foot-and-mouth disease virus 3C protease cleaves NEMO to impair innate immune signaling. / Wang, Dang; Fang, Liurong; Li, Kui; Zhong, Huijuan; Fan, Jinxiu; Ouyang, Chao; Zhang, Huan; Duan, Erzhen; Luo, Rui; Zhang, Zhongming; Liu, Xiangtao; Chen, Huanchun; Xiao, Shaobo.

In: Journal of Virology, Vol. 86, No. 17, 01.09.2012, p. 9311-9322.

Research output: Contribution to journalArticle

Wang, D, Fang, L, Li, K, Zhong, H, Fan, J, Ouyang, C, Zhang, H, Duan, E, Luo, R, Zhang, Z, Liu, X, Chen, H & Xiao, S 2012, 'Foot-and-mouth disease virus 3C protease cleaves NEMO to impair innate immune signaling', Journal of Virology, vol. 86, no. 17, pp. 9311-9322. https://doi.org/10.1128/JVI.00722-12
Wang, Dang ; Fang, Liurong ; Li, Kui ; Zhong, Huijuan ; Fan, Jinxiu ; Ouyang, Chao ; Zhang, Huan ; Duan, Erzhen ; Luo, Rui ; Zhang, Zhongming ; Liu, Xiangtao ; Chen, Huanchun ; Xiao, Shaobo. / Foot-and-mouth disease virus 3C protease cleaves NEMO to impair innate immune signaling. In: Journal of Virology. 2012 ; Vol. 86, No. 17. pp. 9311-9322.
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