Porcine deltacoronavirus nsp15 antagonizes interferon-β production independently of its endoribonuclease activity

Abstract

Porcine deltacoronavirus (PDCoV) is an emerging swine coronavirus causing diarrhea and intestinal damage in nursing piglets. Previous work showed that PDCoV infection inhibits type I interferon (IFN) production. To further identify and characterize the PDCoV-encoded IFN antagonists will broaden our understanding of its pathogenesis. Nonstructural protein 15 (nsp15) encodes an endoribonuclease that is highly conserved among vertebrate nidoviruses (coronaviruses and arteriviruses) and plays a critical role in viral replication and transcription. Here, we found that PDCoV nsp15 significantly inhibits Sendai virus (SEV)-induced IFN-β production. PDCoV nsp15 disrupts the phosphorylation and nuclear translocation of NF-κB p65 subunit, but not antagonizes the activation of transcription factor IRF3. Interestingly, site-directed mutagenesis found that PDCoV nsp15 mutants (H129A, H234A, K269A) lacking endoribonuclease activity also suppress SEV-induced IFN-β production and NF-κB activation, suggesting that the endoribonuclease activity is not required for its ability to antagonize IFN-β production. Taken together, our results demonstrate that PDCoV nsp15 is an IFN antagonist and it inhibits interferon-β production via an endoribonuclease activity-independent mechanism.

Crystal structure of Nsp15 endoribonuclease NendoU from SARS‐CoV‐2

“…More recently, it was proposed that NendoU activity of Nsp15 is responsible for the protein interference with the innate immune response, 11 though other studies indicate that the process is independent of the endonuclease activity. 12 There are also suggestions that Nsp15 degrades viral RNA to hide it from the host defenses. Nevertheless, Nsp15 is essential in coronavirus biology.…”

Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2

“…More recently, it was proposed that NendoU activity of Nsp15 is responsible for the protein interference with the innate immune response (Deng et al, 2017) though other studies indicate that the process is independent of the endonuclease activity (Liu et al, 2019). While initially Nsp15 was thought to directly participate in viral replication, it was later shown that Nsp15-deficient coronaviruses were viable and replicating, rising doubts about the enzyme role in that process.…”

Identification of potential inhibitors of SARS-COV-2 endoribonuclease (EndoU) from FDA approved drugs: a drug repurposing approach to find therapeutics for COVID-19

“…One of these proteins, NSP15 a nidoviral RNA uridylate-specific endoribonuclease (NendoU) containing carboxy-terminal catalytic domain linked to the EndoU family (Deng & Baker, 2018). Previous study has suggested that Nsp15 has crucial role in evasion of host defense mechanism and loss of EndoU function results in protective immune response (Deng & Baker, 2018;Liu et al, 2019). Therefore, Nsp15 is considered critical in coronavirus biology.…”