Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
BBA - Gene Regulatory Mechanisms (v.1809, #11-12)
RNA silencing pathways of plants: Silencing and its suppression by plant DNA viruses by Thomas Hohn; Franck Vazquez (pp. 588-600).
RNA silencing refers to processes that depend on small (s)RNAs to regulate the expression of eukaryotic genomes. In plants, these processes play critical roles in development, in responses to a wide array of stresses, in maintaining genome integrity and in defense against viral and bacterial pathogens. We provide here an updated view on the array of endogenous sRNA pathways, including microRNAs (miRNAs), discovered in the model plant Arabidopsis, which are also the basis for antiviral silencing. We emphasize the current knowledge as well as the recent advances made on understanding the defense and counter-defense strategies evolved in the arms race between plants and DNA viruses on both the nuclear and the cytoplasmic front. This article is part of a Special Issue entitled: MicroRNA's in viral gene regulation.► We describe the different types of RNA silencing pathways that have been discovered in plants. ► We describe how the RNA silencing machinery is involved in defense mechanism against DNA viruses. ► We highlight the different RNA silencing suppressor proteins of DNA viruses that are involved in counteracting the RNA silencing machinery.
Keywords: Caulimoviridae; Geminiviridae; Viroids; Nanoviridae; Silencing; Silencing suppression
Viral induction and suppression of RNA silencing in plants by Hanako Shimura; Vitantonio Pantaleo (pp. 601-612).
RNA silencing in plants and insects can function as a defence mechanism against invading viruses. RNA silencing-based antiviral defence entails the production of virus-derived small interfering RNAs which guide specific antiviral effector complexes to inactivate viral genomes. As a response to this defence system, viruses have evolved viral suppressors of RNA silencing (VSRs) to overcome the host defence. VSRs can act on various steps of the different silencing pathways. Viral infection can have a profound impact on the host endogenous RNA silencing regulatory pathways; alterations of endogenous short RNA expression profile and gene expression are often associated with viral infections and their symptoms. Here we discuss our current understanding of the main steps of RNA-silencing responses to viral invasion in plants and the effects of VSRs on endogenous pathways. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► Viral siRNAs contribute to plant antiviral response upon their incorporation into RISC. ► To counteract this effect, viruses encode viral silencing suppressor of RNA silencing. ► Viral siRNAs and viral silencing suppressors may alter endogenous RNA silencing pathways.
Keywords: Plant virus; vsiRNA; miRNA; DCL; AGO; Viral silencing suppressor
Roles and regulation of microRNAs in cytomegalovirus infection by Lee Tuddenham; Sébastien Pfeffer (pp. 613-622).
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally via binding to complementary sites typically located in the 3′ untranslated regions (UTRs) of their target mRNAs. This ancient regulatory system has been conserved in eukaryotes throughout evolution, and it is therefore unsurprising that certain viruses have evolved to express their own miRNAs. Since the initial discovery of Epstein–Barr virus (EBV) derived miRNAs in 2004, over 230 viral miRNAs have been identified, the majority arising from herpesviruses. Although the functions of most viral miRNAs remain to be elucidated, an increasing number of their cellular and viral targets have been experimentally validated. Due to their non-immunogenic nature, viral miRNAs represent an elegant tool for the virus to evade the host immune system, and likely play a key role in the latent/lytic switch during the viral lifecycle. In this review, we will focus on the interactions of cytomegaloviruses with cellular and viral miRNAs during infection. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► Micro (mi)RNAs are small non coding RNAs that regulate gene expression. ► MiRNAs are found in most eukaryotes and in some viruses. ► Cytomegaloviruses encode for miRNAs playing important roles in infection. ► Some cellular miRNAs are regulated during infection. ► Regulated cellular miRNAs can play pro or antiviral roles.
Keywords: Cytomegalovirus; MiRNA; Herpesvirus; HCMV; MCMV; RCMV
Functions of Kaposi's sarcoma-associated herpesvirus microRNAs by Joseph M. Ziegelbauer (pp. 623-630).
MicroRNAs can modulate gene expression post-transcriptionally by altering mRNA stability and protein translation. Multiple DNA viruses express viral microRNAs and have been shown to modulate expression of host and viral genes. Through various methods of microRNA target identification, we are beginning to understand the various roles of viral miRNAs including viral replication, immune evasion and apoptosis. This review is focused on the roles of microRNAs expressed by Kaposi's sarcoma-associated herpesvirus or human herpesvirus 8. This article is part of a Special Issue entitled: “MicroRNAs in viral gene regulation”.► KSHV expresses 12 pre-microRNAs during latent and lytic infection. ► Microarrays, sequence analysis of miRNAs, and purification of miRNA:mRNA complexes have been used to find miRNA targets. ► Themes of cellular targets targeted by KSHV miRNAs include: cell cycle regulation, innate immunity, and apoptosis.
Keywords: KSHV; miRNA; microRNA; Virus host interaction; Post-transcriptional regulation
EBV-encoded miRNAs by Stephanie Barth; Gunter Meister; Grasser Friedrich A. Grässer (pp. 631-640).
The Epstein–Barr virus (EBV) is an oncogenic Herpes virus involved in the induction of a variety of human tumours. It was the first virus found to encode microRNAs (miRNAs). MiRNAs are short, non-coding RNAs that in most cases negatively regulate gene expression at the post-transcriptional level. EBV-transformed cells express at least 44 mature viral miRNAs that target viral and cellular genes. In addition, EBV-infection severely deregulates the miRNA profile of the host cell. The presently available information indicates that the virus uses its miRNAs to inhibit the apoptotic response of the infected cell as a means to establish a latent infection. Likewise, EBV-encoded miRNAs interfere in the expression of viral genes in order to mask the infected cell from the immune response. Cellular targets of viral miRNAs are involved in protein traffic within the cell and regulate innate immunity. MiRNA profiling of diffuse large B-cell lymphoma (DLBCL) and nasal NK/T-cell lymphoma (NKTL) showed that only 2% of the miRNAs are derived from the virus, while viral miRNAs comprise up to 20% of the total miRNA in nasopharyngeal carcinoma (NPC) and probably contribute to the formation or maintenance of NPC. The presence of viral miRNAs in exosomes raises the fascinating possibility that virus-infected cells regulate gene expression in the surrounding tissue to avert destruction by the immune system. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► Epstein–Barr virus expresses 44 miRNAs and changes the expression of cell miRNAs. ► NPC but not DLBCL and NK/T-cell lymphoma contain high levels of viral miRNAs. ► Viral miRNAs interfere with apoptosis and immune response to infected cells. ► EBV-deregulated cell miRNAs are involved in tumorigenesis. ► EBV-infected cells secreted miRNA-containing exosomes.
Keywords: Epstein–Barr virus; EBV; MicroRNA; MiRNA; BHRF1; BART; Tumorigenesis; Transformation; Gene regulation; Apoptosis; Latency
Mammalian alphaherpesvirus miRNAs by Igor Jurak; Anthony Griffiths; Donald M. Coen (pp. 641-653).
Mammalian alphaherpesviruses are major causes of human and veterinary disease. During productive infection, these viruses exhibit complex and robust patterns of gene expression. These viruses also form latent infections in neurons of sensory ganglia in which productive cycle gene expression is highly repressed. Both modes of infection provide advantageous opportunities for regulation by microRNAs. Thus far, published data regarding microRNAs are available for six mammalian alphaherpesviruses. No microRNAs have yet been detected from varicella zoster virus. The five other viruses—herpes simplex viruses-1 and -2, herpes B virus, bovine herpesvirus-1, and pseudorabies virus—representing both genera of mammalian alphaherpesviruses have been shown to express microRNAs. In this article, we discuss these microRNAs in terms of where they are encoded in the viral genome relative to other viral transcripts; whether they are expressed during productive or latent infection; their potential targets; what little is known about their actual targets and functions during viral infection; and what little is known about the interactions of these viruses with the host microRNA machinery. This article is part of a Special Issue entitled: “MicroRNAs in viral gene regulation”.► We review the published literature on mammalian alphaherpesviruses and microRNAs. ► So far, five of these viruses are known to express microRNAs. ► The most is known about herpes simplex virus microRNAs. ► Some microRNAs are expressed abundantly during latent infections of sensory neurons. ► Transfection studies suggest some microRNAs might promote latency. ► Overall, we know little about microRNA targets and roles in virus infection.
Keywords: miRNAs; Mammalian alphaherpesviruses; Herpes simplex virus; Latency; Varicella zoster virus; Herpes B virus
Roles of avian herpesvirus microRNAs in infection, latency, and oncogenesis by Robin W. Morgan; Joan Burnside (pp. 654-659).
MicroRNAs have been reported for the avian herpesviruses Marek's disease virus 1 (MDV1; oncogenic), Marek's disease virus 2 (MDV2; non-oncogenic), herpesvirus of turkeys (HVT), and infectious laryngotracheitis virus (ILTV). No obvious phylogenetic relationships exist among the avian herpesvirus microRNAs, but the general genomic locations of microRNA clusters are conserved, with microRNAs being located in the repeat regions of the genomes. In some cases, microRNAs are antisense to open reading frames. Among MDV1 field isolates with different virulence properties, microRNAs are highly conserved, and variations that have been observed lie in putative promoter regions. One cluster of MDV1 microRNAs lies upstream of the meq gene, and this cluster is more highly expressed in tumors caused by an extremely virulent MDV1 isolate compared to tumors caused by a less virulent isolate. Several of the avian herpesvirus microRNAs are orthologs of microRNAs in other species. For example, mdv1-miR-M4 shares a seed sequence with gga-miR-155 (also shared with Kaposi sarcoma herpesvirus (KSHV) kshv-miR-K12), mdv2-miR-M21 shares a seed with miR-29b, and hvt-miR-H14 shares a seed sequence with miR-221. Functional analyses of avian herpesvirus microRNAs include a variety of in vitro assays to demonstrate potential function as well as the use of mutants that can exploit the ability to assess phenotypes experimentally in the natural host. This article is part of a Special Issue entitled:MicroRNA's in viral gene regulation.► Avian herpesvirus microRNAs have been reported for MDV1, MDV2, HVT, and ILTV. ► Avian herpesvirus microRNA sequences are unique, but the general genomic locations of microRNA clusters are conserved. ► Avian herpesvirus microRNAs share seed sequences with microRNAs of other species. ► Mdv1-miR-M4 shares a seed sequence with gga-miR-155, and this seed sequence is also shared with kshv-miR-K12. ► The MDV1 meq microRNA cluster is related to MDV1 oncogenicity.
Keywords: Herpesvirus microRNAs; Marek's disease virus; Herpesvirus of turkeys; Avian herpesvirus
Adenovirus and miRNAs by Elena Carnero; James D. Sutherland; Puri Fortes (pp. 660-667).
Adenovirus infection has a tremendous impact on the cellular silencing machinery. Adenoviruses express high amounts of non-coding virus associated (VA) RNAs able to saturate key factors of the RNA interference (RNAi) processing pathway, such as Exportin 5 and Dicer. Furthermore, a proportion of VA RNAs is cleaved by Dicer into viral microRNAs (mivaRNAs) that can saturate Argonaute, an essential protein for miRNA function. Thus, processing and function of cellular miRNAs is blocked in adenoviral-infected cells. However, viral miRNAs actively target the expression of cellular genes involved in relevant functions such as cell proliferation, DNA repair or RNA regulation. Interestingly, the cellular silencing machinery is active at early times post-infection and can be used to control the adenovirus cell cycle. This is relevant for therapeutic purposes against adenoviral infections or when recombinant adenoviruses are used as vectors for gene therapy. Manipulation of the viral genome allows the use of adenoviral vectors to express therapeutic miRNAs or to be silenced by the RNAi machinery leading to safer vectors with a specific tropism. This article is part of a "Special Issue entitled:MicroRNAs in viral gene regulation".► The silencing machinery is active at early times post adenoviral infection. ► Later, Adenoviruses have evolved to both use and block the RNA silencing machinery. ► Adenovirus blocks RNAi by expression of VA RNA, able to saturate Exp5, Dicer and Ago. ► VA RNAs are processed to viral miRNAs able to control the expression of target genes. ► This should be considered in the design of adenoviral vectors for gene therapy.
Keywords: Adenovirus; miRNAs; VA RNA; TIA-1; RNAi
Regulation of cellular miRNA expression by human papillomaviruses by Zhi-Ming Zheng; Xiaohong Wang (pp. 668-677).
High-risk HPV infection leads to aberrant expression of cellular oncogenic and tumor suppressive miRNAs. A large number of these miRNA genes are downstream targets of the transcription factors c-Myc, p53, and E2F and their expression can therefore be modulated by oncogenic HPV E6 and E7. Cervical cancer represents a unique tumor model for understanding how viral E6 and E7 oncoproteins deregulate the expression of the miR-15/16 cluster, miR-17-92 family, miR-21, miR-23b, miR-34a, and miR-106b/93/25 cluster via the E6–p53 and E7–pRb pathways. Moreover, miRNAs may influence the expression of papillomavirus genes in a differentiation-dependent manner by targeting viral RNA transcripts. Cellular miRNAs affecting HPV DNA replication are of great interest and will be a future focus. We are entering an era focusing on miRNA and noncoding RNA, and the studies on HPV and host miRNA interactions will continue shedding more light on our understanding of the HPV life cycle and the mechanistic underpinnings of HPV-induced oncogenesis. This article is part of a Special Issue entitled: “MicroRNAs in viral gene regulation”.► Oncogenic HPV infection deregulates the expression of oncogenic and tumor suppresive miRNAs via E6-p53 and E7-pRb pathways. ► Cellular miRNAs may influence the expression of papillomavirus genes in a differentiation-dependent manner by targeting viral RNAs. ► Cervical cancer provides a unique cancer model for understanding the interplays between HPV and host miRNAs.
Keywords: Abbreviations; HPV; human papillomavirus; miRNA; microRNA; RISC; RNA-induced silencing complex; hTERT; human telomerase reverse transcriptase; BTG3; B-cell translocation gene 3; CIN; cervical intraepithelial neoplasia; uPA; urokinase-type plasminogen activator; DLEU2; deleted in lymphocytic leukemia 2; CLL; chronic lymphocytic leukemia; HFK; human foreskin keratinocytes; RREB1; Ras-responsive element-binding protein 1; PPAR; peroxisome proliferator-activated receptorHuman papillomaviruses; MicroRNAs; Oncogenes; Tumor suppressor genes; Cervical cancer; Gene expression
Role of microRNAs in hepatitis B virus replication and pathogenesis by Wan-Hsin Liu; Shiou-Hwei Yeh; Pei-Jer Chen (pp. 678-685).
The hepatitis B virus (HBV) is a widespread human pathogen and chronic HBV infection is a major risk factor for hepatocellular carcinoma (HCC). The role of microRNA (miRNA) in the replication and pathogenesis was reviewed. So far none of HBV-encoded miRNA has been identified. Cellular miRNAs have shown able to regulate HBV at the transcription level either by targeting to cellular transcriptions factors required for HBV gene expression, or by a directly binding to HBV transcripts. We also summarized the changed patterns of cellular miRNAs from hepatitis B progressing to cirrhosis and then liver cancer. The changing of a few of miRNAs, such as miR-122 or miR-21, were reproduced and worthy of further research by a deep sequencing and functional validation. These HBV-specific miRNAs should potentially become biomarkers for HBV infection and HBV-positive HCC diagnosis. The understanding of miRNA biology paved the way for applying miRNAs-based RNAi against HBV replication with minimal toxicities. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► The role of microRNA in the replication and pathogenesis was reviewed. ► Cellular miRNAs regulate HBV transcription by targeting to cellular transcriptions factors. ► Host miRNAs regulate HBV transcription by a direct binding to HBV transcripts. ► We summarized the changed patterns of cellular miRNAs from hepatitis B progressing. ► These HBV-specific miRNAs should potentially become biomarkers for HBV disease diagnosis.
Keywords: MicroRNA; Hepatitis B virus; Hepatocellular carcinoma; Transcription; Replication; Pathogenesis
MicroRNAs and human retroviruses by Laurent Houzet; Kuan-Teh Jeang (pp. 686-693).
MicroRNAs (miRNAs) are small non-coding RNAs that control a multitude of critical processes in mammalian cells. Increasing evidence has emerged that host miRNAs serve in animal cells to restrict viral infections. In turn, many viruses encode RNA silencing suppressors (RSS) which are employed to moderate the potency of the cell's miRNA selection against viral replication. Some viruses also encode viral miRNAs. In this review, we summarize findings from human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1) that illustrate examples of host cell miRNAs that target the viruses, of RSS encoded by viruses, and of host cell miRNA profile changes that are seen in infected cells. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► Review of cellular miRNAs that have been described to interact with HIV-1 or HTLV-1. ► Review of RSS activities that have been described for HIV-1 and HTLV-1. ► Review of microRNA profile changes in cells after infection by HIV-1 or HTLV-1.
Keywords: MicroRNA; Virus replication; Innate immunity; RNA silencing suppressor; Viral gene expression; Virus–host interaction
MicroRNA in HCV infection and liver cancer by Ajit Kumar (pp. 694-699).
In the more than two-decades since hepatitis C virus (HCV) was identified, there has been considerable improvement in our understanding of virus life cycle due largely to the development of in vitro culture systems for virus replication. Still challenges remain: HCV infection is a major risk factor for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide; yet mechanistic details of HCV infection-associated hepatocarcinogenesis remain incompletely understood. A protective vaccine is not yet available, and current therapeutic options result in sustained virus clearance only in a subset of patients. Recent interest has focused on small non-protein coding RNAs, microRNAs (miRNAs), the dependence of virus replication on miRNAs, and miRNA-regulated genes in liver cancer. Functional analysis of the miRNA-targeted genes in liver cancer has advanced our understanding of the “oncomiRs” and their role in hepatocarcinogenesis. This review focuses on the dependence of HCV replication on miRNA and role of miRNA-targeted tumor suppressor genes as molecular markers of and possible targets for developing oncomiR-targeted therapy of chronic hepatitis and HCC. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► We examined alterations in miRNA expression in liver cancer. ► We examined HCV infection-associated changes in miRNA. ► We examined target validation of miRNA in liver cancer. ► We examined the dependence of HCV replication and hepatocarcinogenesis on oncomiRs. ► Finally, we examined the in vivo model of miRNA replacement therapy in liver cancer and finally we make future speculations for animal model for liver cancer.
Keywords: OncomiR; MicroRNAs in liver cancer; Hepatitis C virus (HCV); Dependence of HCV replication on miRNAs
Drosha processing controls the specificity and efficiency of global microRNA expression by Yong Feng; Xiaoxiao Zhang; Qingfeng Song; Tongbin Li; Yan Zeng (pp. 700-707).
microRNAs (miRNAs) are a large family of approximately 22-nucleotide-long RNAs that regulate gene expression. They are first transcribed as long, primary transcripts, which then undergo a series of processing steps to generate the single-stranded, mature miRNAs. Here, we showed that Drosha cleaved hundreds of human primary miRNA transcript substrates with different efficiencies in vitro. The differential Drosha susceptibility of the primary miRNA transcripts significantly correlated with the expression of the corresponding, mature miRNAs in vivo. Conserved miRNAs were more efficiently expressed in vivo, and their primary transcripts were also better Drosha substrates in vitro. Combining secondary structure prediction and statistical analyses, we identified features in human primary miRNA transcripts that predisposed miRNAs to efficient Drosha processing in vitro as well as to better expression in vivo. We propose that the selectivity of Drosha action contributes greatly to the specificity and efficiency of miRNA biogenesis. Moreover, this study serves as an example of substrate specificity of a biochemical reaction regulating gene expression at a global scale in vivo. This article is part of a Special Issue entitled: MicroRNA's in viral gene regulation.► Human pri-miRNAs are processed by Drosha with different efficiencies in vitro. ► Pri-miRNA processing efficiencies correlate with miRNA expression levels in vivo. ► Conserved pri-miRNAs are better cleaved by Drosha. ► Later-annotated miRNAs tend to be poorer Drosha substrates. ► Structural features in pri-miRNAs predict Drosha processing and miRNA expression.
Keywords: Abbreviations; miRNA; microRNA; pri-miRNA; primary microRNA transcriptmiRNA; Pri-miRNA processing; Drosha; miRNA expression; RNA secondary structure
Viral miRNAs and immune evasion by Isaac W. Boss; Rolf Renne (pp. 708-714).
Viral miRNAs, ~22nt RNA molecules which post-transcriptionally regulate gene expression, are emerging as important tools in immune evasion. Viral infection is a complex process that requires immune evasion in order to establish persistent life-long infection of the host. During this process viruses express both protein-coding and non-coding genes, which help to modulate the cellular environment making it more favorable for infection. In the last decade, it was uncovered that DNA viruses express a diverse and abundant pool of small non-coding RNA molecules, called microRNAs (miRNAs). These virally encoded miRNAs are non-immunogenic and therefore are important tools used to evade both innate and adaptive immune responses. This review aims to summarize our current knowledge of herpesvirus- and polyomavirus-encoded miRNAs, and how they contribute to immune evasion by targeting viral and/or host cellular genes. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► We review currently known viral miRNA targets. ► We examine viral miRNA function in regulating immune evasion. ► The future of viral miRNA research is described.
Keywords: MiRNAs; Viruses; Immune evasion; Viral miRNA targets
Viral miRNAs exploiting the endosomal–exosomal pathway for intercellular cross-talk and immune evasion by D. Michiel Pegtel; Martijn D.B. van de Garde; Jaap M. Middeldorp (pp. 715-721).
The class of persistent gamma-herpesviruses has developed a variety of strategies that exploit host-cell regulatory pathways to ensure a long-lasting, well-balanced infection of their host. However when these pathways are deregulated, an otherwise harmless infection can lead to disease including cancer. We recently demonstrated that the human herpes virus 4 (HHV4) also known as Epstein–Barr virus (EBV), encodes for small regulatory non-coding microRNAs (miRNAs) that can be transferred from an infected cell to uninfected neighboring cells. Upon arrival these miRNAs are functional in the recipient cell, in that they are able to down regulate specific target genes. These secreted miRNAs are transported to recipient cells via small nano-sized vesicles (known as exosomes) that are of endosomal origin, formed as intraluminal vesicles (ILV) inside multivesicular bodies (MVB). One question that needs to be addressed is how viral miRNAs are sorted into these exosomes.Mature miRNAs, including those of viral origin, are loaded into RNA-induced silencing complexes (RISC) for gene silencing via blocking mRNA translation and/or initiating mRNA decay. Recent insights indicate that cytoplasmic RNA granules rich in RISC complexes are closely associated with endosomes. In fact, selective components of RISC, including GW182 and Argonaut proteins, miRNAs and mRNAs are present in exosomes. Thus miRNA function, mRNA stability and exosome-mediated intercellular communication converge at the level of endosomes. Since endosomes can be considered as key intracellular cross-roads that regulate communication of cells with their exterior, including neighboring cells, it is perhaps not surprising that viruses have found means to exploit this pathway to their benefit. Little is known however, how and if (micro) RNA species are specifically sorted into ILVs and what (micro)RNA-binding proteins are involved. Here we discuss recent developments relating to intracellular trafficking and function of miRNA-containing protein complexes that EBV may exploit for promoting or restricting miRNAs sorting into exosomes for intercellular regulatory functions. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► Persistent herpesviruses encode several microRNA species to manipulate their host cell in cis and in trans. ► Viral microRNA utilize host cell processing machinery, which – in part – may involve endosomal sorting. ► A special endosomal microRNA sorting route may exist. ► We have shown that viral microRNA are secreted in endosome-derived exosomes to manipulate neighboring cells. ► Here we discuss new insights in routes for microRNA sorting and secretion using Epstein–Barr virus as model system.
Keywords: Abbreviations; AGO; Argonaute; ds; double stranded; EBV; Epstein–Barr virus; ILV; intraluminal vesicle; mRNA; messenger RNA; miRNA; microRNA; P-body; processing body; RBP; RNA binding protein; RISC; RNA-induced silencing complex; RRM; RNA recognition motif; ESCRT; the endosomal sorting complex required for transportArgonaut; Epstein–Barr virus; Exosome; GW182; MicroRNA; RNA-induced silencing complex
Antiviral strategies in plants based on RNA silencing by Simon-Mateo Carmen Simón-Mateo; Garcia Juan Antonio García (pp. 722-731).
One of the challenges being faced in the twenty-first century is the biological control of plant viral infections. Among the different strategies to combat virus infections, those based on pathogen-derived resistance (PDR) are probably the most powerful approaches to confer virus resistance in plants. The application of the PDR concept not only revealed the existence of a previously unknown sequence-specific RNA-degradation mechanism in plants, but has also helped to design antiviral strategies to engineer viral resistant plants in the last 25 years. In this article, we review the different platforms related to RNA silencing that have been developed during this time to obtain plants resistant to viruses and illustrate examples of current applications of RNA silencing to protect crop plants against viral diseases of agronomic relevance. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► Application of PDR concept to confer virus resistance in plants. ► We review different strategies to engineer viral resistant plants. ► We illustrate examples of current application of RNA silencing to protect crop plants against viral diseases of agronomic relevance.
Keywords: Virus resistance; RNA interference; Pathogen-derived resistance
miRNA cassettes in viral vectors: Problems and solutions by Ying Poi Liu; Ben Berkhout (pp. 732-745).
The discovery of RNA interference (RNAi), an evolutionary conserved gene silencing mechanism that is triggered by double stranded RNA, has led to tremendous efforts to use this technology for basic research and new RNA therapeutics. RNAi can be induced via transfection of synthetic small interfering RNAs (siRNAs), which results in a transient knockdown of the targeted mRNA. For stable gene silencing, short hairpin RNA (shRNA) or microRNA (miRNA) constructs have been developed. In mammals and humans, the natural RNAi pathway is triggered via endogenously expressed miRNAs. The use of modified miRNA expression cassettes to elucidate fundamental biological questions or to develop therapeutic strategies has received much attention. Viral vectors are particularly useful for the delivery of miRNA genes to specific target cells. To date, many viral vectors have been developed, each with distinct characteristics that make one vector more suitable for a certain purpose than others. This review covers the recent progress in miRNA-based gene-silencing approaches that use viral vectors, with a focus on their unique properties, respective limitations and possible solutions. Furthermore, we discuss a related topic that involves the insertion of miRNA-target sequences in viral vector systems to restrict their cellular range of gene expression. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.► miRNA cassettes in viral vectors. ► Adenovirus, adeno-associated, retrovirus, and lentiviral vectors. ► Distinct combinatorial RNAi strategies have been developed to inhibit multiple genes. ► RNAi cassettes in viral vectors may hamper vector production. ► miRNA target sites can be used to restrict gene expression or to study miRNA function.
Keywords: RNAi; siRNA; miRNA; Gene therapy; Viral vector; Vector tropism
MicroRNA-like antivirals by Patrick Arbuthnot (pp. 746-755).
Employing engineered DNA templates to express antiviral microRNA (miRNA) sequences has considerable therapeutic potential. The durable silencing that may be achieved with these RNAi activators is valuable to counter chronic viral infections, such as those caused by HIV-1, hepatitis B, hepatitis C and dengue viruses. Early use of expressed antiviral miRNAs entailed generation of cassettes containing Pol III promoters (e.g. U6 and H1) that transcribe virus-targeting short hairpin RNA mimics of precursor miRNAs. Virus escape from single gene silencing elements prompted later development of combinatorial antiviral miRNA expression cassettes that form multitargeting siRNAs from transcribed long hairpin RNA and polycistronic primary miRNA sequences. Weaker Pol III and Pol II promoters have also been employed to control production of antiviral miRNA mimics, improve dose regulation and address concerns about toxicity caused by saturation of the endogenous miRNA pathway. Efficient delivery of expressed antiviral sequences remains challenging and utilizing viral vectors, which include recombinant adenoviruses, adeno-associated viruses and lentiviruses, has been favored. Investigations using recombinant lentiviruses to transduce CD34+ hematological precursor cells with expressed HIV-1 gene silencers are at advanced stages and show promise in preclinical and clinical trials. Although the use of expressed antiviral miRNA sequences to treat viral infections is encouraging, eventual therapeutic application will be dependent on rigorously proving their safety, efficient delivery to target tissues and uncomplicated large scale preparation of vector formulations. This article is part of a special issue entitled: MicroRNAs in viral gene regulation.► Use of miR-like sequences to silence viral replication is discussed. ► Durable virus gene silencing may be achieved from antiviral miR expression cassettes. ► Multitargeting combinatorial miR expression cassettes limit viral escape. ► Antiviral miR-encoding sequences are compatible with recombinant viral vectors. ► Before antiviral miR therapy is realized, delivery and safety concerns need to be addressed.
Keywords: RNAi; MicroRNA; HIV-1; HBV; HCV; Dengue virus