FIG 1.
Interplay between cellular responses to viral and host dsRNAs, the OAS-RNase L pathway, and antagonism by 2-5A-degrading enzymes. (A) OAS1–3 are IFN-induced dsRNA sensors. Once activated, they synthesize the antiviral substance 2′,5′-oligoadenylate (2-5A) from ATP. 2-5A binds inactive monomeric RNase L, inducing active RNase L dimers, which in turn degrade viral and host single-stranded RNAs. The balance between 2-5A accumulation by OAS enzymes and its degradation by host and viral enzymes determines cell and virus fate and inflammatory responses. (B) Domain structures of viral and cellular 2′,5′-PEs and human PDE12 (an endonuclease/exonuclease/phosphatase [EEP] family member). Features of full-length MERS-CoV NS4b, MHV NS2, RVA SA11 VP3, and Mus musculus AKAP7γ proteins, including a nuclear localization sequence (NLS) and catalytic 2′,5′-PE domains, are compared (modified from reference 24). Positions of conserved histidines within the catalytic domain of 2′,5′-PEs are shown. PKA-RII-α-BD, binding domain for regulatory subunit II (RII) of cAMP-dependent protein kinase A (27). Guanylyltransferase (Gtase) and methyltransferase (Mtase) domains are also shown (25, 29). The mitochondrial-matrix-targeting peptide (MTP) and the catalytic EEP domain of PDE12 are shown (55). Domains shown are not drawn to scale.