Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression

ABSTRACT Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this “enemy within” may encode a viral mimic to induce antiviral immune responses through viral...

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Autores principales:	Bin Zhou, Fei Qi, Fangyi Wu, Hongbo Nie, Yifan Song, Lu Shao, Jingxuan Han, Zhen Wu, Hexige Saiyin, Gang Wei, Penghua Wang, Ting Ni, Feng Qian
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	NF-κB antiviral immune responses endogenous retroviruses gene regulation lncRNA Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3ca250634e4248cf89b6f98a5e7b8d5c
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spelling	oai:doaj.org-article:3ca250634e4248cf89b6f98a5e7b8d5c2021-11-15T16:22:10ZEndogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression10.1128/mBio.00937-192150-7511https://doaj.org/article/3ca250634e4248cf89b6f98a5e7b8d5c2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00937-19https://doaj.org/toc/2150-7511ABSTRACT Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this “enemy within” may encode a viral mimic to induce antiviral immune responses through viral sensors. Here, through whole-genome transcriptome analysis with RNA sequencing (RNA-Seq), we discovered that a full-length ERV-derived long noncoding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), was a positive regulator of NF-κB signaling. lnc-EPAV expression was rapidly upregulated by viral RNA mimics or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a crucial role in antiviral responses. Transcriptome analysis of lnc-EPAV-silenced macrophages showed that lnc-EPAV was critical for RELA target gene expression and innate immune responses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I interferons (IFNs) and, consequently, increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of Rela. Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses. IMPORTANCE Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control Rela transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.Bin ZhouFei QiFangyi WuHongbo NieYifan SongLu ShaoJingxuan HanZhen WuHexige SaiyinGang WeiPenghua WangTing NiFeng QianAmerican Society for MicrobiologyarticleNF-κBantiviral immune responsesendogenous retrovirusesgene regulationlncRNAMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	NF-κB antiviral immune responses endogenous retroviruses gene regulation lncRNA Microbiology QR1-502
spellingShingle	NF-κB antiviral immune responses endogenous retroviruses gene regulation lncRNA Microbiology QR1-502 Bin Zhou Fei Qi Fangyi Wu Hongbo Nie Yifan Song Lu Shao Jingxuan Han Zhen Wu Hexige Saiyin Gang Wei Penghua Wang Ting Ni Feng Qian Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression
description	ABSTRACT Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this “enemy within” may encode a viral mimic to induce antiviral immune responses through viral sensors. Here, through whole-genome transcriptome analysis with RNA sequencing (RNA-Seq), we discovered that a full-length ERV-derived long noncoding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), was a positive regulator of NF-κB signaling. lnc-EPAV expression was rapidly upregulated by viral RNA mimics or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a crucial role in antiviral responses. Transcriptome analysis of lnc-EPAV-silenced macrophages showed that lnc-EPAV was critical for RELA target gene expression and innate immune responses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I interferons (IFNs) and, consequently, increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of Rela. Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses. IMPORTANCE Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control Rela transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.
format	article
author	Bin Zhou Fei Qi Fangyi Wu Hongbo Nie Yifan Song Lu Shao Jingxuan Han Zhen Wu Hexige Saiyin Gang Wei Penghua Wang Ting Ni Feng Qian
author_facet	Bin Zhou Fei Qi Fangyi Wu Hongbo Nie Yifan Song Lu Shao Jingxuan Han Zhen Wu Hexige Saiyin Gang Wei Penghua Wang Ting Ni Feng Qian
author_sort	Bin Zhou
title	Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression
title_short	Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression
title_full	Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression
title_fullStr	Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression
title_full_unstemmed	Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression
title_sort	endogenous retrovirus-derived long noncoding rna enhances innate immune responses via derepressing rela expression
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/3ca250634e4248cf89b6f98a5e7b8d5c
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Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression

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