Meta-Biol

• Pathways

Viral infection produces dsRNA that activates the 2'-5' oligoadenylate synthetase (OAS) to synthesize 5'-triphosphorylated 2'-5'-linked oligoadenylate from ATP. The 2'-5'-linked oligoadenylate with a chemical structure of ppp5'A(2'p5'A)n contain 2 to greater than 5 adenylyl residues (n>2) and are commonly referred to as 2-5A (Kerr IM & Brown RE 1978). The 2-5As bind latent ribonuclease L (RNase L) which in human is encoded by RNASEL gene. RNase L oligomerizes into an active complex capable of cleaving viral ssRNA and cellular ssRNA to inhibit viral replication and spread (Silverman RH 2007; Malathi K et al. 2007; Chakrabarti A et al. 2015). Viruses have developed diverse strategies to escape the host antiviral effects. Several viruses, including some coronaviruses and rotaviruses, encode structurally related 2H phosphoesterases with two conserved His-x-Ser/Thr motifs in their catalytic sites. The NS4b protein of Middle East respiratory syndrome coronavirus (MERS-CoV), the protein VP3 of rotavirus A (RVA), the non-structural 2 (NS2) protein of human respiratory coronavirus HCoV-OC43 and its homologue ns2 protein of mouse hepatitis virus (MHV) possess enzymatic 2′,5-phosphodiesterase (PDE) activity that is capable of antagonizing RNase L and thus countering a potent host antiviral response in mammals (Mazumder R et al., 2002; Zhao L et al. 2012; Zhang R et al. 2013; Silverman RH & Weiss SR 2014; Ogden KM et al. 2015; Sui B et al. 2016; Thornbrough JM et al. 2016; Goldstein SA et al. 2017). The viral 2',5'-PDEs are phylogenetically related to the cellular 2',5'-PDE, a kinase anchoring protein 7 (AKAP7) (Mazumder R et al., 2002; Gold MG et al. 2008; Ogden KM et al. 2015; Brandmann T & Jinek M 2015). Murine AKAP7 was found to cleave the phosphodiester bonds of 2-5A in vitro with rates similar to its viral homologues, ns2 of MHV and VP3 of RVA (Gusho E et al. 2014). Murine AKAP7 (full length and central domain) also effectively degraded 2-5A in intact pIC-transfected human ovarian carcinoma Hey1B cells (Gusho E et al. 2014). The proviral effect of murine AKAP7 required cytoplasmic localization of the PDE domain of AKAP7, whereas full-length AKAP7 was observed only in nuclei. Further studies are needed to identify the subcellular compartment of 2′,5′-PDE activity of AKAP7.

The Reactome event shows a cleavage of 2-5A by RVA protein VP3 as an example of viral 2',5'-PDE activity that antagonizes dsRNA signaling to RNase L.