Viral phosphodiesterases that antagonize double-stranded RNA signaling to RNase L by degrading 2-5A - PubMed (original) (raw)

Review

Viral phosphodiesterases that antagonize double-stranded RNA signaling to RNase L by degrading 2-5A

Robert H Silverman et al. J Interferon Cytokine Res. 2014 Jun.

Abstract

The host interferon (IFN) antiviral response involves a myriad of diverse biochemical pathways that disrupt virus replication cycles at many different levels. As a result, viruses have acquired and evolved genes that antagonize the host antiviral proteins. IFNs inhibit viral infections in part through the 2',5'-oligoadenylate (2-5A) synthetase (OAS)/RNase L pathway. OAS proteins are pathogen recognition receptors that exist at different basal levels in different cell types and that are IFN inducible. Upon activation by the pathogen-associated molecular pattern viral double-stranded RNA, certain OAS proteins synthesize 2-5A from ATP. 2-5A binds to the antiviral enzyme RNase L causing its dimerization and activation. Recently, disparate RNA viruses, group 2a betacoronaviruses, and group A rotaviruses, have been shown to produce proteins with 2',5'-phosphodiesterase (PDE) activities that eliminate 2-5A thereby evading the antiviral activity of the OAS/RNase L pathway. These viral proteins are members of the eukaryotic-viral LigT-like group of 2H phosphoesterases, so named for the presence of 2 conserved catalytic histidine residues. Here, we will review the biochemistry, biology, and implications of viral and cellular 2',5'-PDEs that degrade 2-5A. In addition, we discuss alternative viral and cellular strategies for limiting the activity of OAS/RNase L.

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Figures

**FIG. 1.

Viral activation and antagonism of the OAS/RNase L antiviral pathway in the host cell determines the outcome of infection. dsRNA:OAS1 (PDB ID code 4IG8) (Donovan and others 2013); porcine RNase L in a complex with natural 2-5A and AMP-PNP ligands (PDB ID code 4O1P) (Huang and others 2014); and rat AKAP7 central domain (PDB ID code 2VFY) as an example of a 2′,5′-PDE in the 2H phosphoesterase superfamily (Gold and others 2008). OAS, 2′,5′-oligoadenylate (2-5A) synthetase; dsRNA, double-stranded RNA; PDE, phosphodiesterase.

**FIG. 2.

Homology between rat AKAP7 (PDB ID code 2VFY), MHV ns2 (strain A59), and rotavirus VP3 (strain SA11) [reprinted from Zhang and others (2013)]. (A) PDE domains in MHV ns2 and rotavirus VP3. VP3 domains involved in RNA capping are GTase, guanylyltransferase, and MTase, methyltransferase. (B) Alignments between the x-ray crystal structure of rat AKAP7 (PDB ID code 2VFY) and predicted structures of SA11 VP3-CTD and MHV A59 ns2. The 2 conserved His residues are shown as sticks. PyMol (

http://pymol.org

) was used for molecular graphics. CTD, C-terminal domain; MHV, mouse hepatitis virus.

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Viral phosphodiesterases that antagonize double-stranded RNA signaling to RNase L by degrading 2-5A - PubMed (original) (raw)