Porcine epidemic diarrhea virus 3C-like protease regulates its interferon antagonism by cleaving NEMO

Dang Wang, Liurong Fang, Yanling Shi, Huan Zhang, Li Gao, Guiqing Peng, Huanchun Chen, Kui Li, Shaobo Xiao

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Porcine epidemic diarrhea virus (PEDV) is an enteropathogenic coronavirus causing lethal watery diarrhea in piglets. Since 2010, a PEDV variant has spread rapidly in China, and it emerged in the United States in 2013, posing significant economic and public health concerns. The ability to circumvent the interferon (IFN) antiviral response, as suggested for PEDV, promotes viral survival and regulates pathogenesis of PEDV infections, but the underlying mechanisms remain obscure. Here, we show that PEDV-encoded 3C-like protease, nsp5, is an IFN antagonist that proteolytically cleaves the nuclear transcription factor kappa B (NF-κB) essential modulator (NEMO), an essential adaptor bridging interferon-regulatory factor and NF-κB activation. NEMO is cleaved at glutamine 231 (Q231) by PEDV, and 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 PEDV nsp5 abrogated NEMO cleavage and the inhibition of IFN induction. Structural analysis suggests that several key residues outside the catalytic sites of PEDV nsp5 probably impact NEMO cleavage by modulating potential interactions of nsp5 with their substrates. These data show that PEDV nsp5 disrupts type I IFN signaling by cleaving NEMO. Previously, we and others demonstrated that NEMO is also cleaved by 3C or 3C-like proteinases of picornavirus and artertivirus. Thus, NEMO probably represents a prime target for 3C or 3C-like proteinases of different viruses.

Original languageEnglish (US)
Pages (from-to)2090-2101
Number of pages12
JournalJournal of Virology
Volume90
Issue number4
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Porcine epidemic diarrhea virus
interferons
Interferons
proteinases
Interferon Regulatory Factors
Picornaviridae
3C proteases
transcription factor NF-kappa B
Interferon Type I
Coronavirus
Coronavirinae
Cysteine Proteases
NF-kappa B
cysteine proteinases
Virus Diseases
Glutamine
lethal genes
active sites
glutamine
Antiviral Agents

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Porcine epidemic diarrhea virus 3C-like protease regulates its interferon antagonism by cleaving NEMO. / Wang, Dang; Fang, Liurong; Shi, Yanling; Zhang, Huan; Gao, Li; Peng, Guiqing; Chen, Huanchun; Li, Kui; Xiao, Shaobo.

In: Journal of Virology, Vol. 90, No. 4, 01.01.2016, p. 2090-2101.

Research output: Contribution to journalArticle

Wang, D, Fang, L, Shi, Y, Zhang, H, Gao, L, Peng, G, Chen, H, Li, K & Xiao, S 2016, 'Porcine epidemic diarrhea virus 3C-like protease regulates its interferon antagonism by cleaving NEMO', Journal of Virology, vol. 90, no. 4, pp. 2090-2101. https://doi.org/10.1128/JVI.02514-15
Wang, Dang ; Fang, Liurong ; Shi, Yanling ; Zhang, Huan ; Gao, Li ; Peng, Guiqing ; Chen, Huanchun ; Li, Kui ; Xiao, Shaobo. / Porcine epidemic diarrhea virus 3C-like protease regulates its interferon antagonism by cleaving NEMO. In: Journal of Virology. 2016 ; Vol. 90, No. 4. pp. 2090-2101.
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