Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon

Abstract

The interferon (IFN)-inducible antiviral state is mediated in part by the 2′,5′-oligoadenylate (2-5A) synthetase (OAS)/RNase L system. 2-5A, produced from ATP by OAS proteins in response to viral double-stranded RNA, binds to and activates RNase L. RNase L restricts viral infections by degrading viral and cellular RNA, inducing autophagy and apoptosis, and producing RNA degradation products that amplify production of type I interferons (IFNs) through RIG-I-like receptors. However, the effects of the OAS/RNase L pathway on IFN induction in different cell types that vary in basal levels of these proteins have not been previously reported. Here we report higher basal expression of both RNase L and OAS in mouse macrophages in comparison to mouse embryonic fibroblasts (MEFs). In MEFs, RNase L gene knockout decreased induction of IFN-β by encephalomyocarditis virus infection or poly(rI):poly(rC) (pIC) transfection. In contrast, in macrophages, RNase L deletion increased (rather than decreased) induction of IFN-β by virus or pIC. RNA damage from RNase L in virus-infected macrophages is likely responsible for reducing IFN-β production. Similarly, direct activation of RNase L by transfection with 2-5A induced IFN-β in MEFs but not in macrophages. Also, viral infection or pIC transfection caused RNase L-dependent apoptosis of macrophages but not of MEFs. Our results suggest that cell-type-specific differences in basal levels of OAS and RNase L are determinants of IFN-β induction that could affect tissue protection and survival during viral infections.

Intracellular detection of viral nucleic acids

“…Following activation, RNase L degrades both cellular RNA and vRNA, ultimately limiting virus replication. Interestingly, RNA fragments generated by RNase L have been reported to serve as endogenous ligands for RIG-I, amplifying the IFN response [50,51]. …”

RNase L Activates the NLRP3 Inflammasome during Viral Infections

“…In addition to the direct antiviral effects of RNase L from degradation of viral and cellular RNA, RNase L also initiates signaling events that regulate type I IFN production. RNase L either positively or negatively regulates viral-induction of type I IFNs depending on basal levels of OAS and RNase L in different cell types (Banerjee et al, 2014; Malathi et al, 2007). The RNA cleavage products generated by RNase L often have double-stranded regions (because RNase L is a ssRNA-specific endoribonuclease), a 5′-hydroxyl and a 2′,3′-cyclic phosphoryl group characteristic of metal ion-independent ribonucleases (Cooper et al, 2014).…”

The catcher in the RIG-I

“…for the restriction factor TRIM5 [38], the dsRNA-activated kinase PKR [39], the virus particle release inhibitor tetherin [40], the OAS/RNaseL system [41][42][43], and the virus RNA synthesis inhibitor viperin [44,45], although the mechanisms are sometimes more complex than for RIG-I. In fact, it appears reasonable that a host sensor that clings to a regulatory pathogen structure is hindering viral multiplication, as exemplified by RIG-I binding to the panhandle promoter of influenza virus and to the epsilon stem-loop of HBV.…”