Identification of host DEAD-box RNA helicases that regulate cellular tropism of oncolytic Myxoma virus in human cancer cells

Rahman, Masmudur M.; Bagdassarian, Eugénie; Ali, Mohamed A.; McFadden, Grant

doi:10.1038/s41598-017-15941-1

Cited by 43 publications

(48 citation statements)

References 47 publications

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“…Biochemical studies of HIV-Rev, alone or Rev in combination with RRE RNA, have also identified positive roles for DDX3X, DDX5, DDX17, and DDX21 in HIV infection, although some of these interactions could be indirect [84]. Other DEAD-box helicases have been found genetically by screening to identify genes that affect infection [41,88]. The genetic screening of DEAD-box helicases in poxvirus infection revealed both positive and negative regulation of infection by DEAD-box helicases [88].…”

Section: Summary and Discussionmentioning

confidence: 99%

“…Other DEAD-box helicases have been found genetically by screening to identify genes that affect infection [41,88]. The genetic screening of DEAD-box helicases in poxvirus infection revealed both positive and negative regulation of infection by DEAD-box helicases [88]. And still other studies have focused on changes in gene expression that indicate either cellular innate immune responses or a viral manipulation of the host cell environment [31,89,90].…”

Section: Summary and Discussionmentioning

confidence: 99%

“…IBV [81] dsRNA sensing (with DDX21 and DHX36) [21] Transmissible gastroenteritis virus [18] NF-κB signaling [19] DDX3X Arenavirus [38] JEV [47] HIV [74,84] IFN-β induction (with TBK1) [26] Innate immune signaling [27,28] HBV [36,93] Myxoma virus [88] VACV K7 [34] HBV polymerase [35] HCV 3 UTR [37] DDX5 JEV [47] HIV [84] Myxoma virus [88] DDX6 Negative regulation of ISG induction [66] RVFV, LACV [40] IVB [65] Flaviviruses: sequestered by sfRNA [67,68] DDX10 HIV [89] DDX17 HIV [84,94] RVFV [41] Cofactor for ZAP [43] Tombusviruses [45] DDX18…”

Section: Ddx1mentioning

confidence: 99%

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DEAD-Box Helicases: Sensors, Regulators, and Effectors for Antiviral Defense

Taschuk

Cherry

2020

Viruses

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DEAD-box helicases are a large family of conserved RNA-binding proteins that belong to the broader group of cellular DExD/H helicases. Members of the DEAD-box helicase family have roles throughout cellular RNA metabolism from biogenesis to decay. Moreover, there is emerging evidence that cellular RNA helicases, including DEAD-box helicases, play roles in the recognition of foreign nucleic acids and the modulation of viral infection. As intracellular parasites, viruses must evade detection by innate immune sensing mechanisms and degradation by cellular machinery while also manipulating host cell processes to facilitate replication. The ability of DEAD-box helicases to recognize RNA in a sequence-independent manner, as well as the breadth of cellular functions carried out by members of this family, lead them to influence innate recognition and viral infections in multiple ways. Indeed, DEAD-box helicases have been shown to contribute to intracellular immune sensing, act as antiviral effectors, and even to be coopted by viruses to promote their replication. However, our understanding of the mechanisms underlying these interactions, as well as the cellular roles of DEAD-box helicases themselves, is limited in many cases. We will discuss the diverse roles that members of the DEAD-box helicase family play during viral infections.Viruses 2020, 12, 181 2 of 15 helicases to particular RNAs or proteins; the diversity of these regions accounts for the breadth of function observed within this protein family [7]. As a result of their diversity of binding and function, DEAD-box RNA helicases are involved in all aspects of cellular RNA metabolism, including transcription, splicing, microRNA biogenesis, ribosomal RNA processing, RNA export, translation, RNP granule formation, and decay [10]. Moreover, they are also involved in cellular stress responses, contributing to double-strand break (DSB) repair [11], stress granule formation, and antimicrobial responses [12]. DEAD-Box Helicases in Canonical Innate Immune SensingInnate immune defenses depend upon the recognition of invading pathogens by the host, and viral infections, including RNA viruses, are largely sensed through nucleic acid recognition. RNA viruses present a host cell with various foreign RNA features, such as unique ends, structured RNA elements, or dsRNA replication intermediates, which can be recognized as hallmarks of infection. RNA binding proteins thus play important roles in the sensing of viral infection, and DExD/H helicases are well-suited to recognize structural features characteristic of viral RNAs.The canonical cytoplasmic sensors of viral RNA, the RIG-I-like receptors (RLRs) RIG-I and MDA-5, contain DExD/H-box helicase domains [13]. RIG-I recognizes uncapped viral RNAsand short dsRNAs containing a 5 triphosphate, while MDA-5 binds longer dsRNA replication intermediates [13][14][15]. In addition to the helicase core domain, these proteins contain caspase activation and recruitment domains (CARDs).RNA recognition by these RLRs leads to oligomerization of ...

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Section: Summary and Discussionmentioning

confidence: 99%

Section: Summary and Discussionmentioning

confidence: 99%

Section: Ddx1mentioning

confidence: 99%

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DEAD-Box Helicases: Sensors, Regulators, and Effectors for Antiviral Defense

Taschuk

Cherry

2020

Viruses

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“…As a RNA helicase, DDX5 was shown to be a pro-viral host factor in biosynthesis of several RNA viruses, including HIV and HCV (42). By contrast, DDX5 has antiviral function in myxoma virus biosynthesis (43) and in HBV biosynthesis, by a mechanism not yet understood (7). In our earlier studies, we have observed that DDX5 protein levels become progressively reduced in HBV replicating/infected hepatocytes.…”

Section: Discussionmentioning

confidence: 88%

RNA Helicase DDX5 Negatively Regulates Wnt Signaling and Hepatocyte Reprogramming in Hepatitis B Virus-related Hepatocellular Carcinoma

Mani

Cui

Yan

et al. 2019

Preprint

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Keywords: Hepatitis B Virus, Hepatocellular Carcinoma, RNA helicase DDX5/p68, miR17~92, miR106b~25, RNA-seq, Wnt/β-catenin/ hepatocyte reprogramming/ hepatic cancer stem cell/ antagomirs Word count: 6,200 (without references) ABSTRACT Background and Aims: RNA helicase DEAD box protein 5 (DDX5) is downregulated during hepatitis B virus (HBV) replication, and associates with poor prognosis HBV-related hepatocellular carcinoma (HCC). The aim of this study is to determine the mechanism and significance of DDX5 downregulation for HBV-driven HCC. Approach & Results: We used established cellular models of HBV replication, HBV infection, as well as HBV-related liver tumors. HBV replicating DDX5 knockdown hepatocytes were analyzed by RNAseq; differentially expressed genes were validated by qRT-PCR, and bioinformatic analyses of HCCs from The Cancer Genome Atlas. Our results show reduced expression of DDX5 in HCCs of all etiologies is associated with poor survival. In HBV replicating hepatocytes, downregulation of DDX5 is mediated by miR17~92 and miR106b~25, induced by HBV infection. Increased expression of these miRNAs was quantified in HBV-associated HCCs expressing a hepatic cancer stem cell (hCSC)-like gene signature and reduced DDX5 mRNA, suggesting a role for DDX5 in hCSC formation. Interestingly, DDX5 knockdown in HBV replicating hepatocyte cell lines resulted in hepatosphere formation, sorafenib and cisplatin resistance, Wnt signaling activation and pluripotency gene expression, all characteristics of hCSCs. Moreover, DDX5 knockdown increased viral replication. RNA-seq analyses of HBV-replicating DDX5 knockdown cells, identified enhanced expression of key genes of the Wnt/β-catenin pathway, including Frizzled7 (FZD7) and Matrix Metallopeptidase7 (MMP7), indicative of Wnt signaling activation. Clinically, elevated FZD7 expression correlates with poor patient survival. Importantly, inhibitors to miR17~92 and miR106b~25 restored DDX5 levels and suppressed both Wnt/β-catenin activation and viral replication. Conclusion: DDX5 is a negative regulator of Wnt signaling and hepatocyte reprogramming in HCCs. Restoration of DDX5 levels in HBV-infected patients can exert both antitumor and antiviral effects.

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“…However, DHX9 and DHX36 have also been shown to act as DNA helicases (Linder, 2006; Zhou et al, 2003). The role of DHX9 as an RNA or DNA helicase has been studied in the context of cancer such as colorectal and lung cancer, where DHX9 regulation is cancer-specific (He et al, 2017; Mi et al, 2016; Rahman et al, 2017; Sun et al, 2014). It is also known that DHX9 binds to viral dsRNA in myeloid dendritic cells, leading to the activation of NF-κB and IRF3, along with the production of IFN-α/β (Zhang et al, 2011d).…”

Section: Intracellular Recognition Of Dnamentioning

confidence: 99%

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Matz

Guzman

Goodman

2019

Nucleic Acid Sensing and Immunity - Part B

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Innate immunity, the first line of defense against invading pathogens, is an ancient form of host defense found in all animals, from sponges to humans. During infection, innate immune receptors recognize conserved molecular patterns, such as microbial surface molecules, metabolites produces during infection, or nucleic acids of the microbe’s genome. When initiated, the innate immune response activates a host defense program that leads to the synthesis proteins capable of pathogen killing. In mammals, the induction of cytokines during the innate immune response leads to the recruitment of professional immune cells to the site of infection, leading to an adaptive immune response. While a fully functional innate immune response is crucial for a proper host response and curbing microbial infection, if the innate immune response is dysfunctional and is activated in the absence of infection, autoinflammation and autoimmune disorders can develop. Therefore, it follows that the innate immune response must be tightly controlled to avoid an autoimmune response from host-derived molecules, yet still unencumbered to respond to infection. In this review, we will focus on the innate immune response activated from cytosolic nucleic acids, derived from the microbe or host itself. We will depict how viruses and bacteria activate these nucleic acid sensing pathways and their mechanisms to inhibit the pathways. We will also describe the autoinflammatory and autoimmune disorders that develop when these pathways are hyperactive. Finally, we will discuss gaps in knowledge with regard to innate immune response failure and identify where further research is needed.

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Identification of host DEAD-box RNA helicases that regulate cellular tropism of oncolytic Myxoma virus in human cancer cells

Cited by 43 publications

References 47 publications

DEAD-Box Helicases: Sensors, Regulators, and Effectors for Antiviral Defense

DEAD-Box Helicases: Sensors, Regulators, and Effectors for Antiviral Defense

RNA Helicase DDX5 Negatively Regulates Wnt Signaling and Hepatocyte Reprogramming in Hepatitis B Virus-related Hepatocellular Carcinoma

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

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