RNA triphosphatase DUSP11 enables exonuclease XRN-mediated restriction of hepatitis C virus

Kincaid, Rodney P.; Lam, Victor; Chirayil, Rachel; Randall, Glenn; Sullivan, Christopher S.

doi:10.1073/pnas.1802326115

Cited by 35 publications

(49 citation statements)

References 37 publications

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“…Among the host defense machineries that sense invading pathogens, RIG-I is the key PRR that recognizes the 5 ′ -triphosphate or diphosphate moiety of double-stranded RNA transcripts and in turn activates the antiviral immune defense signaling pathway (Hornung et al 2006). Previous work demonstrated that DUSP11 sequentially removes the γ and β phosphates of triphosphorylated structured host and viral transcripts leaving 5 ′ -monophosphates (Deshpande et al 1999;Burke et al 2016;Kincaid et al 2018). This led us to hypothesize that DUSP11 can modulate the immunogenicity of triphosphorylated transcripts (Burke and Sullivan 2017) and alter the sensitivity of these transcripts to detection by RIG-I.…”

Section: Dusp11 Modulates Rig-i Signaling Sensitivity To Liposomal 5 mentioning

confidence: 99%

“…We used the 5 ′ untranslated region (UTR) of the HCV RNA, as its expression is immunostimulatory (Saito et al 2007). Additionally, we and others had previously demonstrated triphosphatase activity of DUSP11 on HCV RNAs during infection (Amador-Cañizares et al 2018;Kincaid et al 2018). Consistent with RIG-I induction, cationic-lipid-mediated transfection of HCV 5 ′ -triphosphate RNA (referred to here as "5 ′ -ppp-RNA") into the A549 adenocarcinoma human lung epithelial cell line resulted in the induction of both IFNB1 cytokine and ISG15 mRNA transcripts (Fig.…”

Section: Dusp11 Modulates Rig-i Signaling Sensitivity To Liposomal 5 mentioning

confidence: 99%

“…DUSP11 is an RNA triphosphatase that we and others have previously demonstrated to be active on the 5 ′ ends of structured host and viral transcripts (Deshpande et al 1999;Burke et al 2016;Burke and Sullivan 2017;Kincaid et al 2018;Vabret et al 2019). The 5 ′ -triphosphates of hepatitis C virus (HCV) RNAs are converted to monophosphates rendering them susceptible to exonuclease XRNmediated attack (Amador-Cañizares et al 2018;Kincaid et al 2018). A different outcome arises when triphosphorylated RNAP III viral precursor microRNAs (miR-NAs) are processed by DUSP11.…”

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confidence: 99%

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DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

et al. 2020

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Deciphering the mechanisms that regulate the sensitivity of pathogen recognition receptors is imperative to understanding infection and inflammation. Here we demonstrate that the RNA triphosphatase dual-specificity phosphatase 11 (DUSP11) acts on both host and virus-derived 5′-triphosphate RNAs rendering them less active in inducing a RIG-I-mediated immune response. Reducing DUSP11 levels alters host triphosphate RNA packaged in extracellular vesicles and induces enhanced RIG-I activation in cells exposed to extracellular vesicles. Virus infection of cells lacking DUSP11 results in a higher proportion of triphosphorylated viral transcripts and attenuated virus replication, which is rescued by reducing RIG-I expression. Consistent with the activity of DUSP11 in the cellular RIG-I response, mice lacking DUSP11 display lower viral loads, greater sensitivity to triphosphorylated RNA, and a signature of enhanced interferon activity in select tissues. Our results reveal the importance of controlling 5′-triphosphate RNA levels to prevent aberrant RIG-I signaling and demonstrate DUSP11 as a key effector of this mechanism.

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Section: Dusp11 Modulates Rig-i Signaling Sensitivity To Liposomal 5 mentioning

confidence: 99%

Section: Dusp11 Modulates Rig-i Signaling Sensitivity To Liposomal 5 mentioning

confidence: 99%

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confidence: 99%

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DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

et al. 2020

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“…Moreover, knockdown of the pyrophosphatases in combination with the 5′ exonuclease (Xrn1) further increased viral RNA accumulation [ 204 ]. These observations were further confirmed by enhanced HCV replication and decreased miR-122 dependency in DUSP11 knockout cells [ 205 ]. Taken together, these results support a model whereby in the absence of the miR-122, DOM3Z and/or DUSP11 can mediate conversion of the 5′ triphosphate of the HCV genome to a monophosphate.…”

Section: Hepacivirusesmentioning

confidence: 81%

The Diverse Roles of microRNAs at the Host–Virus Interface

Bernier

Sagan

2018

Viruses

107

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MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. Through this activity, they are implicated in almost every cellular process investigated to date. Hence, it is not surprising that miRNAs play diverse roles in regulation of viral infections and antiviral responses. Diverse families of DNA and RNA viruses have been shown to take advantage of cellular miRNAs or produce virally encoded miRNAs that alter host or viral gene expression. MiRNA-mediated changes in gene expression have been demonstrated to modulate viral replication, antiviral immune responses, viral latency, and pathogenesis. Interestingly, viruses mediate both canonical and non-canonical interactions with miRNAs to downregulate specific targets or to promote viral genome stability, translation, and/or RNA accumulation. In this review, we focus on recent findings elucidating several key mechanisms employed by diverse virus families, with a focus on miRNAs at the host–virus interface during herpesvirus, polyomavirus, retroviruses, pestivirus, and hepacivirus infections.

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“…It is envisaged that HCV RNA genomes have evolved to bind the highly abundant liver-specific miR-122 [9] to guarantee persistence in the liver over many years. Mechanistically, miR-122 has been shown to protect the 5’ ppp-containing HCV genome from the action of 5’ RNA triphosphatase DUSP11 [10, 11] and subsequent degradation by 5’ RNA exonucleases XRN1 [12] and XRN2 [13]. Further evidence suggests that miR-122 also participates in the switch of viral RNAs from the translation to the replication phase in the viral life cycle by displacing of RNA binding proteins that enhance viral mRNA translation [14].…”

Section: Introductionmentioning

confidence: 99%

Impact of a Patient-Derived Hepatitis C Viral RNA Genome with a Mutated MicroRNA Binding Site

Mata

Neben

Majzoub

et al. 2018

Preprint

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25Hepatitis C virus (HCV) depends on liver-specific microRNA miR-122 for efficient viral RNA 26 amplification in liver cells. This microRNA interacts with two different conserved sites at the very 27 5' end of the viral RNA, enhancing miR-122 stability and promoting replication of the viral RNA. 28Treatment of HCV patients with oligonucleotides that sequester mir-122 resulted in profound 29 loss of viral RNA in phase II clinical trials. However, some patients accumulated in their sera a 30 viral RNA genome that contained a single cytidine to uridine mutation at the third nucleotide 31 from the 5' genomic end. It is shown here that this C3U variant indeed displayed higher rates of 32 replication than that of wild-type HCV when miR-122 abundance is low in liver cells. However, 33 when miR-122 abundance is high, binding of miR-122 to site 1, most proximal to the 5' end in 34 the C3U variant RNA, is impaired without disrupting the binding of miR-122 to site 2. As a result, 35C3U RNA displays a much lower rate of replication than wild-type mRNA when miR-122 36 abundance is high in the liver. These findings suggest that sequestration of miR-122 leads to a 37 resistance-associated mutation that has only been observed in treated patients so far, and 38 raises the question about the function of the C3U variant in the peripheral blood. 40Author Summary 41With the advent of potent direct-acting antivirals (DAA), hepatitis C virus (HCV) can now be 42 eliminated from the majority of patients, using multidrug therapy with DAAs. However, such 43 DAAs are not available for the treatment of most RNA virus infections. The main problem is the44 high error rate by which RNA-dependent RNA polymerases copy viral RNA genomes, allowing 45 the selection of mutations that are resistant to DAAs. Thus, targeting host-encoded functions 46 that are essential for growth of the virus but not for the host cell offer promising, novel 47 approaches. HCV needs host-encoded microRNA miR-122 for its viral RNA replication in the 48 liver, and depletion of miR-122 in HCV patients results in loss of viral RNA. This study shows 49 3 that a single-nucleotide mutation in HCV allows viral RNA amplification when miR-122 50 abundances are low, concomitant with changes in its tropism. 51 52 Introduction 53 54 Many cell-and virus-encoded microRNAs (miRNAs) regulate the expression of mRNAs by 55 binding to the 3' noncoding regions of target mRNAs. The binding is facilitated by an RNA-56 induced silencing complex (RISC) that mediates base-pair interactions between nucleotides two 57 through seven in the microRNA (seed sequences) and their complementary sites in the target 58 mRNA (seed-match sequences). This targeting event inhibits the translation of the mRNA. In 59 addition, deadenylation at the 3' of the mRNA, followed by decapping and 5' to 3' degradation of 60 the mRNA greatly increases its turnover [1, 2]. 61The growth of hepatitis C virus (HCV), a member of the flaviviridae, is dependent on the 62 most abundant miRNA in the liver, miR-122 [3]. In the liver...

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RNA triphosphatase DUSP11 enables exonuclease XRN-mediated restriction of hepatitis C virus

Cited by 35 publications

References 37 publications

DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

The Diverse Roles of microRNAs at the Host–Virus Interface

Impact of a Patient-Derived Hepatitis C Viral RNA Genome with a Mutated MicroRNA Binding Site

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