108 : Preventing activation of the IFN inducible OAS-RNase L pathway by A-kinase anchoring protein 7 (AKAP7)

The 2′,5′-oligoadenylate (2-5A) synthetase (OAS)-RNase L system is an interferon inducible pathway that blocks virus infections by cleaving viral and cellular single-stranded RNA. Viral dsRNA, produced during infections by both RNA and DNA viruses, activates OAS (a pathogen recognition receptor) resulting in production of 2-5A from ATP, which then activates RNase L leading to RNA cleavage. The factors that determine how cells limit activation of OAS-RNase L pathway to avoid tissue damage are poorly understood. Recently, we reported that the coronavirus, murine hepatitis virus (MHV) strain A59 accessory protein, ns2, blocks the RNase L pathway in macrophages and facilitates the development of hepatitis (Zhao et al., Cell Host & Microbe 11:607–16, 2012). The ns2 protein is a 2H phosphoesterase family member with two conserved His-x-Thr/Ser motifs that eliminates 2-5A, the activator of RNase L, through its 2′,5′-phosphodiesterase activity. Here we will show that cellular A-kinase anchoring protein 7 (AKAP7), another 2H phosphoesterase and homolog of ns2, has a similar enzymatic activity that degrades 2-5A. AKAP7 thus potentially provides the host cell with a mechanism for eliminating excess 2-5A and thus terminating RNase L activation. Accordingly, RNase L-mediated cleavage of rRNA in response to poly (rI):poly (rC) activation of OAS was suppressed by AKAP7 as determined in RNA chip analyses. In addition, cellular levels of active 2-5A were reduced by AKAP7 expression as determined by fluorescence resonance energy transfer assays for RNase L activation. These findings suggest that AKAP7 may be cytoprotective by preventing sustained activation of RNase L.