The Role of Coronavirus RNA-Processing Enzymes in Innate Immune Evasion

Abstract

Viral RNA sensing triggers innate antiviral responses in humans by stimulating signaling pathways that include crucial antiviral genes such as interferon. RNA viruses have evolved strategies to inhibit or escape these mechanisms. Coronaviruses use multiple enzymes to synthesize, modify, and process their genomic RNA and sub-genomic RNAs. These include Nsp15 and Nsp16, whose respective roles in RNA capping and dsRNA degradation play a crucial role in coronavirus escape from immune surveillance. Evolutionary studies on coronaviruses demonstrate that genome expansion in Nidoviruses was promoted by the emergence of Nsp14-ExoN activity and led to the acquisition of Nsp15- and Nsp16-RNA-processing activities. In this review, we discuss the main RNA-sensing mechanisms in humans as well as recent structural, functional, and evolutionary insights into coronavirus Nsp15 and Nsp16 with a view to potential antiviral strategies.

Keywords: SARS-CoV-2; coronavirus; immune evasion; innate immunity; viral RNA sensing.

Figure 1

Innate immune evasion by coronaviruses. Upon viral RNA sensing, the expression of type I and III interferons (IFNs) is activated. IFNs are secreted in an autocrine and paracrine manner to induce the expression of interferon-stimulated genes (ISGs) through the STAT1/2 signaling pathway. RNA-processing enzymes Nsp15 and Nsp16 are essential for the escape from viral RNA sensing, while other expressed non-structural or accessory proteins inhibit the STAT1/2 pathway. The regions encoding for the NSP15 and NSP16 proteins are highlighted with black color and their 3D structures are displayed in cartoon representation based on PDB files 6WXC and 6WVN respectively.

Figure 2

Genome expansion in Nidoviruses and the evolution of viral RNA capping and endonucleolytic cleavage of dsRNA intermediates. (A) Genomic organization and expression of ExoN NendoU, N7-MT, and 2′-MT domains in representative members of nidoviruses. (B) The functional role of Nsp15 and Nsp16 proteins in coronavirus life cycle. (A) n, 3′ polyA sequence; dsRNA, double-stranded RNA; SAM, S-adenosyl methionine SAH, S-adenosyl homocysteine.

Figure 3

Inhibitors of SARS-CoV-2 Nsp15 and Nsp16 proteins. (A). Structure of Nsp16 in Complex with 7-methyl-GpppA (GTA) and S-Adenosylmethionine (PDB: 6WVN). (B) Binding of Sinefungin (SFG) in SARS-Cov-2 NSP16 (PDB: 6WKQ). (C). Structure of NSP15 Endoribonuclease from SARS CoV-2 in the Complex with drug Tipiracil (PDB: 6WXC).