ABSTRACT The 2′,5′-oligoadenylate (2-5A)-dependent endoribonuclease, RNase L, is a principal mediator of the interferon (IFN) antiviral response. Therefore, the regulation of cellular levels of 2-5A is a key point of control in antiviral innate immunity. Cellular 2-5A levels are determined by IFN-inducible 2′,5′-oligoadenylate synthetases (OASs) and by enzymes that degrade 2-5A. Importantly, many coronaviruses (CoVs) and rotaviruses encode 2-5A-degrading enzymes, thereby antagonizing RNase L and its antiviral effects. A-kinase-anchoring protein 7 (AKAP7), a mammalian counterpart, could possibly limit tissue damage from excessive or prolonged RNase L activation during viral infections or from self-double-stranded RNAs that activate OAS. We show that these enzymes, members of the two-histidine phosphoesterase (2H-PE) superfamily, constitute a subfamily referred here as 2′,5′-PEs. 2′,5′-PEs from the mouse CoV mouse hepatitis virus (MHV) (NS2), Middle East respiratory syndrome coronavirus (MERS-CoV) (NS4b), group A rotavirus (VP3), and mouse (AKAP7) were investigated for their evolutionary relationships and activities. While there was no activity against 3′,5′-oligoribonucleotides, they all cleaved 2′,5′-oligoadenylates efficiently but with variable activity against other 2′,5′-oligonucleotides. The 2′,5′-PEs are shown to be metal ion-independent enzymes that cleave trimer 2-5A (2′,5′-p 3 A 3 ) producing mono- or diadenylates with 2′,3′-cyclic phosphate termini. Our results suggest that the elimination of 2-5A might be the sole function of viral 2′,5′-PEs, thereby promoting viral escape from innate immunity by preventing or limiting the activation of RNase L.
【저자키워드】 coronavirus, Innate immunity, interferons, rotavirus, RNase L, 2-5A, AKAP7, OAS, two-histidine phosphoesterase, 【초록키워드】 viral infection, coronavirus, Antiviral, antiviral effects, MERS-CoV, RNA, Protein, IFN, MHV, Enzymes, cellular, antiviral response, RNase, rotavirus, Middle East, phosphate, mouse hepatitis virus, Activation, Regulation, tissue damage, enzyme, activities, viral escape, CoVs, trimer, respiratory syndrome coronavirus, while, mammalian, limit, shown, investigated, the interferon, activate, producing, evolutionary relationship, cleaved, cleave, degrade, mouse CoV, NS2, NS4b, 【제목키워드】 Innate,