Viral 2',5'-PDE cleaves 2'-5' oligoadenylates

Stable Identifier
R-HSA-9615042
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Rotavirus A
Compartment
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Viral infection produces dsRNA that activates the 2'-5' oligoadenylate synthetase (OAS) to synthesize 5'-triphosphorylated 2'-5'-linked oligoadenylate from ATP. The 2'-5'-linked oligoadenylate with a chemical structure of ppp5'A(2'p5'A)n contain 2 to greater than 5 adenylyl residues (n>2) and are commonly referred to as 2-5A (Kerr IM & Brown RE 1978). The 2-5As bind latent ribonuclease L (RNase L) which in human is encoded by RNASEL gene. RNase L oligomerizes into an active complex capable of cleaving viral ssRNA and cellular ssRNA to inhibit viral replication and spread (Silverman RH 2007; Malathi K et al. 2007; Chakrabarti A et al. 2015). Viruses have developed diverse strategies to escape the host antiviral effects. Several viruses, including some coronaviruses and rotaviruses, encode structurally related 2H phosphoesterases with two conserved His-x-Ser/Thr motifs in their catalytic sites. The NS4b protein of Middle East respiratory syndrome coronavirus (MERS-CoV), the protein VP3 of rotavirus A (RVA), the non-structural 2 (NS2) protein of human respiratory coronavirus HCoV-OC43 and its homologue ns2 protein of mouse hepatitis virus (MHV) possess enzymatic 2′,5-phosphodiesterase (PDE) activity that is capable of antagonizing RNase L and thus countering a potent host antiviral response in mammals (Mazumder R et al., 2002; Zhao L et al. 2012; Zhang R et al. 2013; Silverman RH & Weiss SR 2014; Ogden KM et al. 2015; Sui B et al. 2016; Thornbrough JM et al. 2016; Goldstein SA et al. 2017). The viral 2',5'-PDEs are phylogenetically related to the cellular 2',5'-PDE, a kinase anchoring protein 7 (AKAP7) (Mazumder R et al., 2002; Gold MG et al. 2008; Ogden KM et al. 2015; Brandmann T & Jinek M 2015). Murine AKAP7 was found to cleave the phosphodiester bonds of 2-5A in vitro with rates similar to its viral homologues, ns2 of MHV and VP3 of RVA (Gusho E et al. 2014). Murine AKAP7 (full length and central domain) also effectively degraded 2-5A in intact pIC-transfected human ovarian carcinoma Hey1B cells (Gusho E et al. 2014). The proviral effect of murine AKAP7 required cytoplasmic localization of the PDE domain of AKAP7, whereas full-length AKAP7 was observed only in nuclei. Further studies are needed to identify the subcellular compartment of 2′,5′-PDE activity of AKAP7.

The Reactome event shows a cleavage of 2-5A by RVA protein VP3 as an example of viral 2',5'-PDE activity that antagonizes dsRNA signaling to RNase L.

Literature References
PubMed ID Title Journal Year
24905202 Viral phosphodiesterases that antagonize double-stranded RNA signaling to RNase L by degrading 2-5A

Silverman, RH, Weiss, SR

J. Interferon Cytokine Res. 2014
23878220 Homologous 2',5'-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity

Zhang, R, Jha, BK, Ogden, KM, Dong, B, Zhao, L, Elliott, R, Patton, JT, Silverman, RH, Weiss, SR

Proc. Natl. Acad. Sci. U.S.A. 2013
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
oligoribonucleotidase activity of Protein VP3 [cytosol]
Physical Entity
Activity
Disease
Name Identifier Synonyms
viral infectious disease 934 arbovirus infectious disease, Viral disease, Viral infection NOS, Viral infection, unspecified (disorder), Viral infection NOS, Viral disease (disorder), Viral disease, Viral infection NOS (disorder), Viral Infection, virus infection, virus infection, Viral: [infection NOS] or [illness]
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