Antagonism of the Interferon-Induced OAS-RNase L Pathway by Murine Coronavirus ns2 Protein Is Required for Virus Replication and Liver Pathology

Zhao, Ling; Jha, Babal K.; Wu, Ashley Y; Elliott, Ruth; Ziebuhr, John; Gorbalenya, Alexander E.; Silverman, Robert H.; Weiss, Susan R.

doi:10.1016/j.chom.2012.04.011

Cited by 263 publications

(369 citation statements)

References 59 publications

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“…As we reported previously (7), ns2 degrades (2′-5′)p 3 A 3 to (2′-5′)p 3 A 2 and 5′-AMP, and then the diadenylate (2′-5′)p 3 A 2 is degraded to 5′-AMP and 5′-ATP (Fig. 1C).…”

Section: Resultssupporting

confidence: 86%

Murine AKAP7 Has a 2′,5′-Phosphodiesterase Domain That Can Complement an Inactive Murine Coronavirus ns2 Gene

Gusho

Zhang

Jha

et al. 2014

mBio

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Viral 2′,5′-phosphodiesterases (2′,5′-PDEs) help disparate RNA viruses evade the antiviral activity of interferon (IFN) by degrading 2′,5′-oligoadenylate (2-5A) activators of RNase L. A kinase anchoring proteins (AKAPs) bind the regulatory subunits of protein kinase A (PKA) to localize and organize cyclic AMP (cAMP) signaling during diverse physiological processes. Among more than 43 AKAP isoforms, AKAP7 appears to be unique in its homology to viral 2′,5′-PDEs. Here we show that mouse AKAP7 rapidly degrades 2-5A with kinetics similar to that of murine coronavirus (mouse hepatitis virus [MHV]) strain A59 ns2 and human rotavirus strain WA VP3 proteins. To determine whether AKAP7 could substitute for a viral 2′,5′-PDE, we inserted AKAP7 cDNA into an MHV genome with an inactivated ns2 gene. The AKAP7 PDE domain or N-terminally truncated AKAP7 (both lacking a nuclear localization motif), but not full-length AKAP7 or a mutant, AKAP7H185R, PDE domain restored the infectivity of ns2 mutant MHV in bone marrow macrophages and in livers of infected mice. Interestingly, the AKAP7 PDE domain and N-terminally deleted AKAP7 were present in the cytoplasm (the site of MHV replication), whereas full-length AKAP7 was observed only in nuclei. We suggest the possibility that viral acquisition of the host AKAP7 PDE domain might have occurred during evolution, allowing diverse RNA viruses to antagonize the RNase L pathway.

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Section: Resultssupporting

confidence: 86%

Murine AKAP7 Has a 2′,5′-Phosphodiesterase Domain That Can Complement an Inactive Murine Coronavirus ns2 Gene

Gusho

Zhang

Jha

et al. 2014

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“…Further supporting this conclusion, expression of the MHV PDE, NS2, a potent RNase L antagonist (Zhao et al, 2012), but not its inactive mutant, enables recovery of viable ADAR1 KO cells while knockdown of NS2 in ADAR1 KO cells leads to cell death (Figure 5). Based on these results, we propose that RNase L has a predominant role in promoting cell death by dsRNA (Figure 1).…”

Section: Discussionmentioning

confidence: 69%

Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line

Banerjee

Goldstein

et al. 2017

eLife

141

149

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ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation of ADAR1 leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice, Adar1 mutations are embryonic lethal but are rescued by mutation of the Mda5 or Mavs genes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of ADAR1 mutation are unknown. We show that the cell-lethal phenotype of ADAR1 deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the RNASEL gene or by expression of the RNase L antagonist, murine coronavirus NS2 accessory protein. Our result demonstrate that ablation of RNase L activity promotes survival of ADAR1 deficient cells even in the presence of MDA5 and MAVS, suggesting that the RNase L system is the primary sensor pathway for endogenous dsRNA that leads to cell death.DOI: http://dx.doi.org/10.7554/eLife.25687.001

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“…Surprisingly, our data suggested that the most C-terminal 3CL pro cleavage site in CavV pp1a ( 2386 E|N 2387 ) was located more than 110 residues upstream of the CavV pp1a C-terminus. In most other nidovirus polyproteins (except for toroviruses, which have a phosphodiesterase domain in this polyprotein region; Smits et al, 2006;Snijder et al, 2003;Zhao et al, 2012], conserved 3CL pro cleavage sites are located a few residues upstream of the pp1a C-terminus (Ziebuhr et al, 2000) and the ribosomal frameshift (RFS) signal involved in pp1ab expression (Brierley, 1995;Brierley et al, 1987Brierley et al, , 1989Herold & Siddell, 1993). Proteolytic cleavage at this most C-terminal pp1a cleavage site has two major consequences: it removes a small peptide from the pp1a C-terminal processing product and generates the N-terminus of the nidovirus RdRp-containing processing product, the latter containing a few ORF1a-encoded N-terminal residues (reviewed by de Groot et al, 2012b;Gorbalenya et al, 2006;Snijder et al, 2013;Ziebuhr et al, 2000).…”

mentioning

confidence: 99%

Proteolytic processing of mesonivirus replicase polyproteins by the viral 3C-like protease

Blanck

Ziebuhr

2016

Journal of General Virology

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Mesoniviridae are a family of insect RNA viruses that diverged profoundly from other families of the Nidovirales. Mesonivirus replicative proteins are produced from large polyprotein (pp) precursors (pp1a and pp1ab) through proteolytic cleavage by the viral 3C-like protease (3CL pro ) and, possibly, other proteases. Using recombinant forms of the Cavally virus 3CL pro and pp1a/pp1ab-derived substrates, we characterized 3CL pro cleavage sites in mesonivirus polyproteins. Our data lead us to suggest that 3CL pro cleaves the central and C-proximal regions of mesonivirus pp1a/pp1ab at 12 conserved sites. Compared to other nidovirus homologues, the mesonivirus 3CL pro features a distinct substrate specificity, with asparagine at P2 being a major specificity determinant. Furthermore, we provide evidence that expression of the ORF1b-encoded part of pp1ab involves a À1 ribosomal frameshift at a conserved GGAUUUU heptanucleotide sequence in the ORF1a/1b overlap region. Taken together, the study identifies critical steps in the expression and maturation of mesonivirus replicative proteins.

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Antagonism of the Interferon-Induced OAS-RNase L Pathway by Murine Coronavirus ns2 Protein Is Required for Virus Replication and Liver Pathology

Cited by 263 publications

References 59 publications

Murine AKAP7 Has a 2′,5′-Phosphodiesterase Domain That Can Complement an Inactive Murine Coronavirus ns2 Gene

Murine AKAP7 Has a 2′,5′-Phosphodiesterase Domain That Can Complement an Inactive Murine Coronavirus ns2 Gene

Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line

Proteolytic processing of mesonivirus replicase polyproteins by the viral 3C-like protease

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