nsp15 cleaves viral poly(U)-RNA

Stable Identifier
R-HSA-9755252
Type
Reaction [uncertain]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
double membrane vesicle viral factory outer membrane, cytoplasm
ReviewStatus
5/5
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nsp15 cleaves viral poly(U)-RNA
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Nonstructural protein 15 of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2 nsp15) is a nidoviral RNA uridylate‐specific endoribonuclease (EndoU) with the C‐terminal catalytic NendoU domain (Kim Y et al. 2020, 2021; Frazier MN et al. 2021). SARS-CoV-2 nsp15 shares 88% sequence identity and 95% sequence similarity with nsp15 of SARS-CoV-1 (Kim Y et al. 2020). Similar to its SARS-CoV-1 orthologue, nsp15 of SARS-CoV-2 forms a hexamer that consists of a dimer of trimers (Kim Y et al. 2020; Pillon MC et al. 2021). Nsp15 proteins from Middle East respiratory syndrome coronavirus (MERS-CoV) and murine hepatitis virus (MHV) also function as hexamers (Ricagno S et al. 2006; Bhardwaj K et al. 2008; Xu X et la. 2006; Kim Y et al. 2020). In vitro, the EndoU activity of SARS-CoV-1 nsp15 cleaves single-stranded (ss) and double-stranded (ds) RNAs with a preference for the 3′-ends of uridylates (Ivanov KA et al. 2004; Bhardwaj K et al. 2004, 2006). SARS-CoV-2 nsp15 was found to bind and hydrolyze 4, 7, and 20 nucleotide long RNA (Kim Y et al. 2021). Structural alignment of the catalytic site residues and RNA ligands of SARS-CoV-2 nsp15 and ribonuclease A (RNase A) suggests that nsp15 cleaves RNA through a ribonuclease A (RNase A)-like mechanism producing 2′‐3′ cyclic phosphodiester and 5′‐hydroxyl termini on the RNA products (Kim Y et al. 2021). Mutations in the SARS-CoV-2 nsp15 catalytic site resulted in reduced or abrogated RNA cleavage (Frazier MN et al. 2021). The presence of Mn2+ enhanced nsp15 activity in vitro (Kim Y et al. 2021). Biochemical studies with nsp15 originated from MERS-CoV or MHV suggest that coronavirus nsp15 functions in conjunction with the viral RTC (Zhang L et al. 2018; Athmer J et al. 2017). Further, MHV or human coronavirus 229E (HCoV-229E) that contain a catalytically-deficient nsp15 mutants stimulated MDA5 (IFIH1)-mediated IFN production and activated host dsRNA sensors such as PKR and RNase L in human and mouse cells (Kindler E et al. 2017; Deng X et al. 2017). Together these data suggest that coronavirus nsp15 proteins, including SARS-CoV-2 nsp15, bind and cleave viral polyuridine (polyU) RNA sequences degrading dsRNA at the site of viral RNA synthesis. The nsp15-mediated cleavage of RNA is thought to prevent an activation of host dsRNA sensors dampening IFN production in mammalian cells (Kindler E et al. 2017; Deng X et al. 2017; Hackbar M et al. 2020).

This Reactome event shows SARS-CoV-2 nsp15-mediated cleavage of viral poly(U) dsRNA and ssRNA substrates within the viral RTC.

Literature References
PubMed ID Title Journal Year
34403466 Characterization of SARS2 Nsp15 nuclease activity reveals it's mad about U

Dillard, LB, Borgnia, MJ, Wilson, IM, Frazier, MN, Stewart, ZD, Stanley, RE, Deterding, LJ, Pillon, MC, Williams, JG, Perera, L, Krahn, JM

Nucleic Acids Res 2021
32304108 Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2

Maltseva, NI, Joachimiak, A, Godzik, A, Jedrzejczak, R, Kim, Y, Endres, M, Wilamowski, M, Michalska, K

Protein Sci. 2020
33504779 Cryo-EM structures of the SARS-CoV-2 endoribonuclease Nsp15 reveal insight into nuclease specificity and dynamics

Borgnia, MJ, Sobhany, M, Frazier, MN, Williams, JG, Hsu, AL, Gordon, J, Dandey, VP, Dillard, LB, Kocaman, S, Hayne, CK, Stewart, ZD, Stanley, RE, Deterding, LJ, Pillon, MC, Perera, L, Krahn, JM

Nat Commun 2021
33564093 Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2

Wower, J, Kang, S, Randall, G, Nicolaescu, V, Joachimiak, A, Chang, C, Jedrzejczak, R, Kim, Y, Wilamowski, M, Maltseva, N, Michalska, K

Commun Biol 2021
Participants
Input
Output
Participates
as an event of
Catalyst Activity

RNA endonuclease activity, producing 3'-phosphomonoesters of RTC [double membrane vesicle viral factory outer membrane]

Physical Entity
RTC [double membrane vesicle viral factory outer membrane] (Severe acute respiratory syndrome coronavirus 2)
Activity
RNA endonuclease activity, producing 3'-phosphomonoesters (GO:0016892)
Disease
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
Authored
Shamovsky, V  (2021-10-27)
Reviewed
Messina, F  (2022-02-18)
Created
Shamovsky, V  (2021-10-07)
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