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 degr...

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Autores principales:	Shuvojit Banerjee, Arindam Chakrabarti, Babal Kant Jha, Susan R. Weiss, Robert H. Silverman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d38515ba7d9a40ea8020f408e657a9a9
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spelling	oai:doaj.org-article:d38515ba7d9a40ea8020f408e657a9a92021-11-15T15:45:13ZCell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon10.1128/mBio.00856-142150-7511https://doaj.org/article/d38515ba7d9a40ea8020f408e657a9a92014-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00856-14https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE Type I interferons (IFNs) such as IFN-β are essential antiviral cytokines that are often required for animal survival following infections by highly pathogenic viruses. Therefore, host factors that regulate type I IFN production are critically important for animal and human health. Previously we reported that the OAS/RNase L pathway amplifies antiviral innate immunity by enhancing IFN-β production in mouse embryonic fibroblasts and in virus-infected mice. Here we report that high basal levels of OAS/RNase L in macrophages reduce, rather than increase, virus induction of IFN-β. RNA damage and apoptosis caused by RNase L were the likely reasons for the decreased IFN-β production in virus-infected macrophages. Our studies suggest that during viral infections, the OAS/RNase L pathway can either enhance or suppress IFN production, depending on the cell type. IFN regulation by RNase L is suggested to contribute to tissue protection and survival during viral infections.Shuvojit BanerjeeArindam ChakrabartiBabal Kant JhaSusan R. WeissRobert H. SilvermanAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 2 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Shuvojit Banerjee Arindam Chakrabarti Babal Kant Jha Susan R. Weiss Robert H. Silverman Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon
description	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. IMPORTANCE Type I interferons (IFNs) such as IFN-β are essential antiviral cytokines that are often required for animal survival following infections by highly pathogenic viruses. Therefore, host factors that regulate type I IFN production are critically important for animal and human health. Previously we reported that the OAS/RNase L pathway amplifies antiviral innate immunity by enhancing IFN-β production in mouse embryonic fibroblasts and in virus-infected mice. Here we report that high basal levels of OAS/RNase L in macrophages reduce, rather than increase, virus induction of IFN-β. RNA damage and apoptosis caused by RNase L were the likely reasons for the decreased IFN-β production in virus-infected macrophages. Our studies suggest that during viral infections, the OAS/RNase L pathway can either enhance or suppress IFN production, depending on the cell type. IFN regulation by RNase L is suggested to contribute to tissue protection and survival during viral infections.
format	article
author	Shuvojit Banerjee Arindam Chakrabarti Babal Kant Jha Susan R. Weiss Robert H. Silverman
author_facet	Shuvojit Banerjee Arindam Chakrabarti Babal Kant Jha Susan R. Weiss Robert H. Silverman
author_sort	Shuvojit Banerjee
title	Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon
title_short	Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon
title_full	Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon
title_fullStr	Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon
title_full_unstemmed	Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon
title_sort	cell-type-specific effects of rnase l on viral induction of beta interferon
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/d38515ba7d9a40ea8020f408e657a9a9
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Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon

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