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.

Intranasal administration of a single dose of a candidate live attenuated vaccine derived from an NSP16-deficient SARS-CoV-2 strain confers sterilizing immunity in animals

“…The NSPs form the replication and transcription complex (RTC), which replicates viral genomic RNA and transcribes viral subgenomic RNAs. Two catalytic components of the RTC, NSP14 and NSP16, are critical for the methylation of the 5′ cap of viral mRNAs, a process that allows evasion of immune detection by making the viral RNAs indistinguishable from host mRNA [ 23 ]. NSP14 possesses S-adenosylmethionine (SAM)-dependent methyltransferase (MTase) activity, which facilitates the addition of a methyl group to the guanosine at N7 to generate a Cap-0 structure on viral mRNA.…”

Recent insights into the structure and function of coronavirus ribonucleases

“…The function of Nsp15 within the RTC is much less clear; Nsp15 co‐localizes with the other RTC members and molecular modeling suggests that Nsp15 could function as a central scaffold for the entire RTC [ 20 , 21 , 22 ]. Nsp14 and Nsp15 have also been shown to be important for evasion of the host immune response specifically by blocking the accumulation of double‐stranded (ds) RNA intermediates that form during replication (recently reviewed in Refs [ 23 , 24 ]). Nucleic acids, including the dsRNA replication intermediate and the negative‐strand poly‐U sequence in CoVs, form a class of pathogen‐associated molecular patterns (PAMPs), which stimulate the innate immune system.…”

How do the severe acute respiratory coronavirus 2 (SARS-CoV-2) and its variants escape the host protective immunity and mediate pathogenesis?

“…Thus the initial PAMP-PRR interaction Martin-Sancho et al ( 2021 ), van der Made et al ( 2020 ), Wan et al ( 2020 ) Avoidance of innate immunity during viral entry A defective interferon (IFN) response to SARS-CoV-2 by host that is resulted due to the impairment of expression of the IFN-stimulated genes (ISGs) encoding mainly LY6E , whose product stops the viral replication onward Martin-Sancho et al ( 2021 ), Kikkert ( 2020 ), Snijder et al ( 2020 ) Downregulation of several ISGs which specifically interferes the entry of SARS-CoV-2 spike (S) protein Suppression of IFN-1 induced anti-viral state triggers hyper-inflammation and COVID-19 severity Wan et al ( 2020 ), Snijder et al ( 2020 ) Defective endosomal factors which are actually directed to inhibit the entry of SARS-CoV-2 Loss of control to inhibit SARS-CoV-2 replication Loss of expression of the required RNA binding proteins which are supposed to hinder the viral RNA synthesis Martin-Sancho et al ( 2021 ), V'kovski et al ( 2021 ) Lack of production of the cluster of endoplasmic reticulum (ER)/Golgi-resident anti-viral ISGs which are dedicated to suppress the genes required for viral assembly Curved membrane vesicles Such modification of intracellular membranes makes the SARS-CoV-2 RNA replication easier Klein et al ( 2020 ) Cap-snatching process The host capping enzymes may be employed by SARS-CoV-2, resulting in viral mRNAs consisting of both the host capped small RNA (addition of a 7-methyl guanosine; and lacking of the 2′-O-methylation) and the virus-encoded RNA. Thus, the SARS-CoV-2 RNAs may escape recognition by the host innate immune RNA sensors Beyer and Forero ( 2022 ), Mandilara et al ( 2021 ), Kikkert ( 2020 ), Dai et al ( 2020 ) Avoidance of recognition by the melanoma differentiation-associated protein (MDA5) sensor Avoid recognition by the MDA5 sensor which controls the innate immune response to SARS-CoV-2 in ...…”

“…It’s interesting to note that in order to make viral proteins, most viruses have been reported to hijack the host translational machineries, i.e., the host capping enzymes and utilizing the capped host mRNAs as substrates (Dai et al 2020 ). The short, 5′-capped transcripts produced by the cellular DNA-dependent RNA polymerase II from the host mRNAs is the process that is known as the cap-snatching mechanism (Mandilara et al 2021 ; Kikkert 2020 ). Such cap-snatching process has been observed in several positive stranded RNA viruses and in the Influenza virus which possess the viral mRNAs comprising both the host capped small RNA (addition of a 7-methyl guanosine; and lacking of the 2′-O-methylation) and the virus-encoded RNA (Dai et al 2020 ; Drappier et al 2015 ).…”