MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses

Zeng, Ming; Hu, Zeping; Shi, Xiaolei; Li, Xiaohong; Zhan, Xiaoming; Li, Xiao Dong; Wang, Jianhui; Choi, Jin Huk; Wang, Kuan wen; Purrington, Tiana; Tang, Miao; Fina, Maggy; DeBerardinis, Ralph J.; Moresco, Eva Marie Y.; Pedersen, Gabriel Kristian; McInerney, Gerald M.; Hedestam, Gunilla B. Karlsson; Chen, Zhijian J.; Beutler, Bruce

doi:10.1126/science.346.6216.1486

Cited by 98 publications

(100 citation statements)

References 35 publications

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“…The described interactions between infectious viruses and the transposons that comprise the bulk of mammalian host genomes are consistent with the hypothesis that transposons are symbionts integral to genomic stress responses (McClintock 1984), including antiviral immune responses (Zeng et al 2014;Yu et al 2015). The piRNA system in mammals is known to silence quasi-nonself transposon nucleic acids; our observations raise the hypothesis that, as for CRISPR/Cas in prokaryotes, truly exogenous nonself nucleic acids from infecting viruses can be targeted by piRNA-like RNAs, but that this requires genetic information flow in an unexpected retrotransposon-dependent manner (Nuñez et al 2015).…”

Section: Discussionmentioning

confidence: 51%

piRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals

Parrish

Fujino

Shiromoto

et al. 2015

RNA

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Endogenous bornavirus-like nucleoprotein elements (EBLNs) are sequences within vertebrate genomes derived from reverse transcription and integration of ancient bornaviral nucleoprotein mRNA via the host retrotransposon machinery. While species with EBLNs appear relatively resistant to bornaviral disease, the nature of this association is unclear. We hypothesized that EBLNs could give rise to antiviral interfering RNA in the form of PIWI-interacting RNAs (piRNAs), a class of small RNA known to silence transposons but not exogenous viruses. We found that in both rodents and primates, which acquired their EBLNs independently some 25-40 million years ago, EBLNs are present within piRNA-generating regions of the genome far more often than expected by chance alone (P = 8 × 10 −3 -6 × 10 −8 ). Three of the seven human EBLNs fall within annotated piRNA clusters and two marmoset EBLNs give rise to bona fide piRNAs. In both rats and mice, at least two of the five EBLNs give rise to abundant piRNAs in the male gonad. While no EBLNs are syntenic between rodent and primate, some of the piRNA clusters containing EBLNs are; thus we deduce that EBLNs were integrated into existing piRNA clusters. All true piRNAs derived from EBLNs are antisense relative to the proposed ancient bornaviral nucleoprotein mRNA. These observations are consistent with a role for EBLN-derived piRNA-like RNAs in interfering with ancient bornaviral infection. They raise the hypothesis that retrotransposon-dependent virus-to-host gene flow could engender RNA-mediated, sequence-specific antiviral immune memory in metazoans analogous to the CRISPR/Cas system in prokaryotes.

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Section: Discussionmentioning

confidence: 51%

piRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals

Parrish

Fujino

Shiromoto

et al. 2015

RNA

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“…Anomalous expression of the murine repetitive element GSAT was shown to trigger transcription of the repeat-dependent activated IFN response, which can regulate apoptosis-related cell death. Similarly, when expressed, endogenous retroviral RNA can activate the innate immune response via several pathways (13). Altogether, these studies suggest that certain ncRNAs may also have attributes of immunostimulatory nucleic acid sequences.…”

mentioning

confidence: 81%

“…Remarkably, we found hundreds of sequences falling outside of this distribution. Many have high use of CpG dinucleotides, including a set of endogenous viruses (SI Appendix, Table S2) recently implicated in the innate immune response in tumors (13). We conclude that although the portions of the noncoding regions typically expressed as lncRNAs have motif use patterns similar to RNA from coding regions, there are many genomic regions with atypical motif use that are not transcribed in normal cells or tissues.…”

Section: Cancer-enriched Noncoding Repeat Rna May Have Anomalous Motifmentioning

confidence: 93%

Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Tanne

Muniz

Puzio-Kuter

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is often indicative of pathogenassociated RNA. For instance, we show that the tumor-associated human repeat human satellite repeat II (HSATII) is enriched in motifs containing CpG dinucleotides in AU-rich contexts that most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNAs functions as immunostimulatory "self-agonists" and directly activates cells of the mononuclear phagocytic system to produce proinflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We propose that the innate response in tumors may partially originate from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors, and thereby assign a previously unidentified danger-associated function to a set of dark matter repetitive elements. These findings potentially reconcile several observations concerning the role of ncRNA expression in cancers and their relationship to the tumor microenvironment.noncoding RNA | genome evolution | cancer immunology

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“…We did so in order to examine if NF-κB activation could induce HERV expression, based on reports that HERVs could have κB response elements in their LTRs [25] and that murine ERVs are responsive to NF-κB following BCR activation [36]. However, IL-1β (10 pg/mL) treatment only induced expression of HK2 env and pol (Fig.…”

Section: The Hdac Inhibitors Vorinostat and Panobinostat Do Not Incrementioning

confidence: 99%

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

et al. 2016

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Background: While antiretroviral therapies have improved life expectancy and reduced viral loads in HIV-1-positive individuals, the cessation of treatment results in a rebound of viral replication. This suggests that a reservoir of latently-infected cells remains within these patients, the identity of which is ill-defined and therefore difficult to target therapeutically. Current strategies are aimed at using drugs such as histone deacetylase (HDAC) inhibitors to induce the expression of latent HIV-1 proviruses in order to activate and ultimately eradicate this reservoir of infected cells. One concern with the use of HDAC inhibitors is that they could up-regulate human endogenous retroviruses (HERVs), as well as HIV-1, with potentially pathophysiological consequences. Results:In this study, we analysed the transcription of HERV genes in HIV-1 latency T cell (J-LAT 8.4) and monocyte (U1) models following treatment with the HDAC inhibitors, vorinostat, panobinostat and romidepsin. We examined the expression of HERV-K (HML-2) env and pol, as well as the co-opted genes HERV-W env (syncytin-1), HERV-FRD env (syncytin-2), in these cell lines. Finally, we investigated HERV expression in primary human T cells. Conclusions:We show that HDAC inhibitors did not substantially increase the transcription of the analysed HERV env or pol genes, suggesting that histone acetylation is not crucial for controlling HERV expression in these experimental models and in ex vivo primary human T cells. Importantly, this indicates that unwanted HERV expression does not appear to be a barrier to the use of HDAC inhibitors in HIV-1 cure strategies.

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MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses

Cited by 98 publications

References 35 publications

piRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals

piRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals

Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Human endogenous retrovirus (HERV) expression is not induced by treatment with the histone deacetylase (HDAC) inhibitors in cellular models of HIV-1 latency

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