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

Abstract

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.

Molecular Evolution of Human Coronavirus Genomes

“…Interestingly, both VP3 and NS2a show two motifs that are characteristic of the 2H-PDE family and share very little sequence similarity to the PDE domain of a cellular protein, AKAP7 [24] ( Figure 2B). AKAP7 and the viral PDEs display structural homology ( Figure 2B), and murine AKAP7 can complement an inactive MHV NS2a gene [25]. From an evolutionary standpoint, these observations suggest that: (i) beta-CoVs and rotaviruses have independently acquired PDE activities; and (ii) AKAP7 served as the source gene in both viral genera ( Figure 2B).…”

cGAS and CD-NTase enzymes: structure, mechanism, and evolution

“…Interestingly, animal receptors including STING and the mouse oxidoreductase RECON recognize diverse bacterial CD-NTase products, indicating that cross-kingdom CD-NTase signaling may be an important component of host-microbe interactions [19 ,21,52]. Specific nuclease and phosphodiesterase enzymes have been identified that degrade CD-NTase product signals [23,[53][54][55][56][57][58], and it is likely that many CD-NTase pathways require dedicated mechanisms for signal inactivation in animal and bacterial cells ( Table 1).…”

Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L

“…The activity of the OASs is normally low to allow for housekeeping protein synthesis, but it increases in the presence of viral or host dsRNA molecules (8). 2-5A has an antiviral effect, against which some viruses have evolved 2-5A antagonist genes that are essential for infection (9)(10)(11)(12)(13)(14)(15)(16).…”