Oncotarget

Research Papers:

The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/ MDA5 activation

Zhen Ding, Liurong Fang _, Shuangling Yuan, Ling Zhao, Xunlei Wang, Siwen Long, Mohan Wang, Dang Wang, Mohamed Frahat Foda and Shaobo Xiao

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Oncotarget. 2017; 8:49655-49670. https://doi.org/10.18632/oncotarget.17912

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Abstract

Zhen Ding1,2, Liurong Fang1,2, Shuangling Yuan1,2, Ling Zhao1,2, Xunlei Wang1,2, Siwen Long1,2, Mohan Wang1,2, Dang Wang1,2, Mohamed Frahat Foda1,2 and Shaobo Xiao1,2

1State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China

2Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China

Correspondence to:

Liurong Fang, email: fanglr@mail.hzau.edu.cn

Keywords: coronavirus, nucleocapsid protein, innate immunity evasion, type I interferon, PACT

Received: October 27, 2016     Accepted: May 01, 2017     Published: May 17, 2017

ABSTRACT

Coronaviruses (CoVs) are a huge threat to both humans and animals and have evolved elaborate mechanisms to antagonize interferons (IFNs). Nucleocapsid (N) protein is the most abundant viral protein in CoV-infected cells, and has been identified as an innate immunity antagonist in several CoVs, including mouse hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV. However, the underlying molecular mechanism(s) remain unclear. In this study, we found that MHV N protein inhibited Sendai virus and poly(I:C)-induced IFN-β production by targeting a molecule upstream of retinoic acid-induced gene I (RIG-I) and melanoma differentiation gene 5 (MDA5). Further studies showed that both MHV and SARS-CoV N proteins directly interacted with protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein that can bind to RIG-I and MDA5 to activate IFN production. The N–PACT interaction sequestered the association of PACT and RIG-I/MDA5, which in turn inhibited IFN-β production. However, the N proteins from porcine epidemic diarrhea virus (PEDV) and porcine reproductive and respiratory syndrome virus (PRRSV), which are also classified in the order Nidovirales, did not interact and counteract with PACT. Taken together, our present study confirms that both MHV and SARS-CoV N proteins can perturb the function of cellular PACT to circumvent the innate antiviral response. However, this strategy does not appear to be used by all CoVs N proteins.


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