SARS-CoV-1 dsRNA intermediates bind DDX58

Stable Identifier
R-HSA-9693589
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Human SARS coronavirus
Compartment
Synonyms
SARS-CoV-1 dsRNA binds to RIG-I
ReviewStatus
5/5
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Double‑stranded RNA (dsRNA), synthesized during the course of infection by RNA viruses as a byproduct of replication and transcription, acts as a potent trigger of the host innate antiviral response. In the cytoplasm of the infected cell, the presence of viral dsRNA is recognized by retinoic‑acid inducible gene I (RIG‑I)‑like receptors (RLR), such as antiviral innate immune response receptor RIG-I (RIG‑I, also known as DEAD box protein 58, DDX58). DDX58 recognizes short dsRNAs. The dsRNA length must be 19 bp or longer to induce DDX58‑mediated type I interferon (IFN)‑mediated response (Schlee M et al. 2009; Marq JB et al. 2010). Viral RNAs activates DDX58 by binding to its RNA helicase domain. This provokes a change in DDX58 conformation exposing the caspase activation and recruitment domain (CARD) leading to DDX58 oligomerization, allowing it to interact with mitochondrial antiviral‑signaling protein (MAVS, IPS‑1). Host mRNAs are 5'‑capped and 2'‑O‑methylated. These mRNA characteristics enable host mRNAs to escape from self‑recognition by DDX58 (Schlee M et al. 2009; Schmidt A et al. 2009; Schuberth‑Wagner C et al. 2015). Severe acute respiratory syndrome coronavirus type 1 (SARS‑CoV‑1) has developed a strategy to avoid recognition by DDX58. Viral dsRNA replication intermediates derived from SARS‑CoV‑1 were shown to associate with the replicase‑transcriptase complex (RTC) bound to double membrane vesicles, which protected viral RNA from host sensors (Stertz S et al. 2007; Knoops K et al. 2008). In addition, nonstructural protein 14 (nsp14) of SARS‑CoV‑1 possesses guanine‑N7‑methyltransferase activity that can mimic host 5'‑cap structure on the viral RNA (Chen Y et al. 2009). Nsp16 of SARS‑CoV-1 further modifies this cap with its 2’‑O‑methyl‑transferase activity, allowing the virus to efficiently evade recognition by DDX58 (RIG‑I) and MDA5 (Chen Y et al. 2011; Menachery VD et al. 2014; Daffis S et al. 2010). SARS‑CoV‑1 with a mutated nsp16 displays reduced virulence that is dependent on MDA5 sensing (Menachery VD et al. 2014). Mutating nsp16 also attenuates virulence in Middle East respiratory syndrome (MERS)‑CoV and reduces disease severity in infected mice (Menachery VD et al. 2017). Thus, nsp16 is critical to alter the type I IFN‑mediated innate antiviral response in SARS and MERS infections.

The amino acid sequence alignment of nsp14 and nsp16 from SARS-CoV-2 and of SARS-CoV-1 showed 95 and 93% of sequence identity respectively (Yoshimoto FK 2020). Structural studies suggest that properties and biological functions of SARS-CoV-2 nsp14 and nsp16 could be very similar to these of SARS-CoV-1 (Decroly E et al. 2011; Chen Y et al. 2011; Rosas-Lemus M et al. 2020; Lin S et al. 2020; Viswanathan T et al. 2020).

Literature References
PubMed ID Title Journal Year
15208624 The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

Taira, K, Shinobu, N, Yoneyama, M, Fujita, T, Miyagishi, M, Kikuchi, M, Imaizumi, T, Natsukawa, T

Nat Immunol 2004
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