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

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.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) antagonizes interferon-β production via blocking IPS-1 and RIG-I

“…RIG-I is also the aim for many coronaviruses. The nucleocapsid proteins of MHV and SARS-CoV antagonist IFN-β by attenuation of PACT-mediated RIG-I activation (Ding et al, 2017). The accessory protein NS6 encoded by PDCoV antagonized IFN-β production by interfering with the binding of RIG-I to double-stranded RNA .…”

Antiviral activity of iridoid glycosides extracted from Fructus Gardeniae against influenza A virus by PACT-dependent suppression of viral RNA replication

“…In an RNP reconstitution assay, knocking down PACT in IAV-infected A549 cells enhanced vRNA production and the subsequent IFN response 59 . Of interest, there might be interplay between PACT and other viral molecules, such as the herpes simplex virus type 1 (HSV-1) Us11 protein, Middle East respiratory syndrome coronavirus (MERS-CoV) 4a and the nucleocapsid of the Ebola virus (EBOV) VP35, mouse hepatitis virus (MHV) N proteins and influenza A virus NS1 [60][61][62][63] . Hence, PACT might be a common target to counteract innate immunity response induced by different viruses with the potential to be developed into a new broad-spectrum antiviral drug.…”

Differential induction of type I interferon by type I and type II feline coronaviruses in vitro

“…The mechanism of inhibition of type I IFN response by IFNβ has been closely investigated in several viruses. For example, in TGEV, PEDV, murine hepatitis virus, severe acute respiratory syndrome (SARS)-CoV, and middle east respiratory syndrome (MERS)-CoV, it has been reported that structural proteins, excluding non-structural proteins and spike protein, inhibit IFNβ production (Case et al, 2018(Case et al, , 2016Ding et al, 2017;Hu et al, 2017;Li et al, 2016;Lu et al, 2011;Lui et al, 2016;Zhang et al, 2016). However, it is unclear whether type I IFN responses are inhibited by FCoV.…”