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ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections

Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is a...

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Autores principales: Ramnani, Barkha, Manivannan, Praveen, Jaggernauth, Sarah, Malathi, Krishnamurthy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922175/
https://www.ncbi.nlm.nih.gov/pubmed/33670646
http://dx.doi.org/10.3390/v13020315
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author Ramnani, Barkha
Manivannan, Praveen
Jaggernauth, Sarah
Malathi, Krishnamurthy
author_facet Ramnani, Barkha
Manivannan, Praveen
Jaggernauth, Sarah
Malathi, Krishnamurthy
author_sort Ramnani, Barkha
collection PubMed
description Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated by double-stranded RNA to synthesize unique oligoadenylates, 2-5A, to activate RNase L. RNase L exerts an antiviral effect by cleaving diverse RNA substrates, limiting viral replication; many viruses have evolved mechanisms to counteract the OAS/RNase L pathway. Here, we show that the ATP-binding cassette E1 (ABCE1) transporter, identified as an inhibitor of RNase L, regulates RNase L activity and RNase L-induced autophagy during viral infections. ABCE1 knockdown cells show increased RNase L activity when activated by 2-5A. Compared to parental cells, the autophagy-inducing activity of RNase L in ABCE1-depleted cells is enhanced with early onset. RNase L activation in ABCE1-depleted cells inhibits cellular proliferation and sensitizes cells to apoptosis. Increased activity of caspase-3 causes premature cleavage of autophagy protein, Beclin-1, promoting a switch from autophagy to apoptosis. ABCE1 regulates autophagy during EMCV infection, and enhanced autophagy in ABCE1 knockdown cells promotes EMCV replication. We identify ABCE1 as a host protein that inhibits the OAS/RNase L pathway by regulating RNase L activity, potentially affecting antiviral effects.
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spelling pubmed-79221752021-03-03 ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections Ramnani, Barkha Manivannan, Praveen Jaggernauth, Sarah Malathi, Krishnamurthy Viruses Article Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated by double-stranded RNA to synthesize unique oligoadenylates, 2-5A, to activate RNase L. RNase L exerts an antiviral effect by cleaving diverse RNA substrates, limiting viral replication; many viruses have evolved mechanisms to counteract the OAS/RNase L pathway. Here, we show that the ATP-binding cassette E1 (ABCE1) transporter, identified as an inhibitor of RNase L, regulates RNase L activity and RNase L-induced autophagy during viral infections. ABCE1 knockdown cells show increased RNase L activity when activated by 2-5A. Compared to parental cells, the autophagy-inducing activity of RNase L in ABCE1-depleted cells is enhanced with early onset. RNase L activation in ABCE1-depleted cells inhibits cellular proliferation and sensitizes cells to apoptosis. Increased activity of caspase-3 causes premature cleavage of autophagy protein, Beclin-1, promoting a switch from autophagy to apoptosis. ABCE1 regulates autophagy during EMCV infection, and enhanced autophagy in ABCE1 knockdown cells promotes EMCV replication. We identify ABCE1 as a host protein that inhibits the OAS/RNase L pathway by regulating RNase L activity, potentially affecting antiviral effects. MDPI 2021-02-18 /pmc/articles/PMC7922175/ /pubmed/33670646 http://dx.doi.org/10.3390/v13020315 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ramnani, Barkha
Manivannan, Praveen
Jaggernauth, Sarah
Malathi, Krishnamurthy
ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections
title ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections
title_full ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections
title_fullStr ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections
title_full_unstemmed ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections
title_short ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections
title_sort abce1 regulates rnase l-induced autophagy during viral infections
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922175/
https://www.ncbi.nlm.nih.gov/pubmed/33670646
http://dx.doi.org/10.3390/v13020315
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