Interplay between viruses and host mRNA degradation

Messenger RNA degradation is a fundamental cellular process that plays a critical role in regulating gene expression by controlling both the quality and the abundance of mRNAs in cells. Naturally, viruses must successfully interface with the robust cellular RNA degradation machinery to achieve an optimal balance between viral and cellular gene expression and establish a productive infection in the host. In the past several years, studies have discovered many elegant strategies that viruses have evolved to circumvent the cellular RNA degradation machinery, ranging from disarming the RNA decay pathways and co-opting the factors governing cellular mRNA stability to promoting host mRNA degradation that facilitates selective viral gene expression and alters the dynamics of host–pathogen interaction. This review summarizes the current knowledge of the multifaceted interaction between viruses and cellular mRNA degradation machinery to provide an insight into the regulatory mechanisms that influence gene expression in viral infections. This article is part of a Special Issue entitled: RNA Decay mechanisms.     

病毒RNA如何逃避宿主细胞的降解

细胞RNA的降解机制不仅在基因表达调节方面具有重要作用,而且也是一种重要的病毒防御机制. 作为一种必须在细胞内增殖的微生物,病毒已经进化出了多种机制,以保护它们的RNA免被宿主细胞降解,如病毒RNA模拟宿主细胞mRNA的结构、形成磷脂包膜、形成局部二级结构、结合自己或宿主细胞编码的蛋白质和编码核酸酶增强宿主细胞mRNA降解等. 本文主要论述了病毒RNA逃避宿主细胞降解的方式,并对其应用前景进行了展望,尤其是在研发抗病毒药物方面的应用前景.     

Functional similarity analysis of human virus-encoded miRNAs

miRNAs are a class of small RNAs that regulate gene expression via RNA silencing machinery. Some viruses also encode miRNAs, contributing to the complex virus-host interactions. A better understanding of viral miRNA functions would be useful in designing new preventive strategies for treating diseases induced by viruses. To meet the challenge for how viruses module host gene expression by their encoded miRNAs, we measured the functional similarities among human viral miRNAs by using a method we reported previously. Higher order functions regulated by viral miRNAs were also identified by KEGG pathway analysis on their targets. Our study demonstrated the biological processes involved in virus-host interactions via viral miRNAs. Phylogenetic analysis suggested that viral miRNAs have distinct evolution rates compared with their corresponding genome.     

Tethering KSRP, a decay-promoting AU-rich element-binding protein, to mRNAs elicits mRNA decay

Inherently unstable mRNAs contain AU-rich elements (AREs) in their 3' untranslated regions that act as mRNA stability determinants by interacting with ARE-binding proteins (ARE-BPs). We have destabilized two mRNAs by fusing sequence-specific RNA-binding proteins to KSRP, a decay-promoting ARE-BP, in a tethering assay. These results support a model that KSRP recruits mRNA decay machinery/factors to elicit decay. The ability of tethered KSRP to elicit mRNA decay depends on functions of known mRNA decay enzymes. By targeting the Rev response element of human immunodeficiency virus type 1 by using Rev-KSRP fusion protein, we degraded viral mRNA, resulting in a dramatic reduction of viral replication. These results provide a foundation for the development of novel therapeutic strategies to inhibit specific gene expression in patients with acquired or hereditary diseases.     

Virus-derived small interfering RNAs at the core of plant-virus interactions

Once a virus enters a cell, viral double-stranded RNA (dsRNA) is targeted by the RNA silencing machinery to initiate a cascade of regulatory events directed by viral small interfering RNAs (vsiRNAs). Recent genetic and functional studies along with the high-throughput sequencing of vsiRNAs have shed light on the genetic and structural requirements for virus targeting, the origins and compositions of vsiRNAs and their potential for controlling gene expression. The precise nature of the triggering molecules of virus-induced RNA silencing or the targeting constraints for viral genome recognition and processing represent outstanding questions that will be discussed in this review. The contribution of vsiRNAs to antiviral defense and host genome modifications has profound implications for our understanding of viral pathogenicity and host specificity in plants.     

Translational control of coronaviruses

Coronaviruses represent a large family of enveloped RNA viruses that infect a large spectrum of animals. In humans, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic and is genetically related to SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV), which caused outbreaks in 2002 and 2012, respectively. All viruses described to date entirely rely on the protein synthesis machinery of the host cells to produce proteins required for their replication and spread. As such, virus often need to control the cellular translational apparatus to avoid the first line of the cellular defense intended to limit the viral propagation. Thus, coronaviruses have developed remarkable strategies to hijack the host translational machinery in order to favor viral protein production. In this review, we will describe some of these strategies and will highlight the role of viral proteins and RNAs in this process.     

What Happens Inside Lentivirus or Influenza Virus Infected Cells: Insights into Regulation of Cellular and Viral Protein Synthesis

Efficient manipulation of the regulatory mechanisms controlling host cell gene expression provides the means for productive infection by animal viruses. Upon infecting the host cell, viruses must: (i) bypass the cellular antiviral defense mechanisms to prevent the translational blocks imposed by the interferon pathway; and (ii) effectively “hijack” the host protein synthetic machinery into mass production of virion protein components. The multicomponent regulatory nature of cellular gene expression has provided the means of selecting for a diverse range of mechanisms utilized by animal viruses to ensure that replication efficiency is maintained throughout the virus life cycle. One important research component of the careful examination of gene regulation is those studies that focus on elucidating the mechanisms by which viruses control mRNA translation during host cell infection. Much of the work in our laboratory has focused on elucidating the strategies by which human immunodeficiency virus type 1 and influenza virus regulate protein synthesis during infection. Here we describe the ways in which these two distinctly different RNA viruses ensure the selective and efficient translation of their viral mRNAs in infected cells. These strategies include circumvention of the deleterious effects associated with activation of the interferon-induced protein kinase, PKR. Herein we describe our methodologies designed to elucidate the translational regulation in cells infected by these viruses. We conclude with a brief summary of new directions, utilizing these methods, taken toward understanding the translational control mechanisms imposed by these viral systems, and how our studies of virally infected cells have allowed us to identify growth-regulating components of normal, uninfected cells.     

Severe Acute Respiratory Syndrome Coronavirus nsp1 Facilitates Efficient Propagation in Cells through a Specific Translational Shutoff of Host mRNA

Severe acute respiratory syndrome (SARS) coronavirus (SCoV) is an enveloped virus containing a single-stranded, positive-sense RNA genome. Nine mRNAs carrying a set of common 5' and 3' untranslated regions (UTR) are synthesized from the incoming viral genomic RNA in cells infected with SCoV. A nonstructural SCoV nsp1 protein causes a severe translational shutoff by binding to the 40S ribosomal subunits. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNA. However, the mechanism by which SCoV viral proteins are efficiently produced in infected cells in which host protein synthesis is impaired by nsp1 is unknown. In this study, we investigated the role of the viral UTRs in evasion of the nsp1-mediated shutoff. Luciferase activities were significantly suppressed in cells expressing nsp1 together with the mRNA carrying a luciferase gene, while nsp1 failed to suppress luciferase activities of the mRNA flanked by the 5'UTR of SCoV. An RNA-protein binding assay and RNA decay assay revealed that nsp1 bound to stem-loop 1 (SL1) in the 5'UTR of SCoV RNA and that the specific interaction with nsp1 stabilized the mRNA carrying SL1. Furthermore, experiments using an SCoV replicon system showed that the specific interaction enhanced the SCoV replication. The specific interaction of nsp1 with SL1 is an important strategy to facilitate efficient viral gene expression in infected cells, in which nsp1 suppresses host gene expression. Our data indicate a novel mechanism of viral gene expression control by nsp1 and give new insight into understanding the pathogenesis of SARS.     

Characterisation of the Semliki Forest Virus-host cell interactome reveals the viral capsid protein as an inhibitor of nonsense-mediated mRNA decay

The positive-sense, single-stranded RNA alphaviruses pose a potential epidemic threat. Understanding the complex interactions between the viral and the host cell proteins is crucial for elucidating the mechanisms underlying successful virus replication strategies and for developing specific antiviral interventions. Here we present the first comprehensive protein-protein interaction map between the proteins of Semliki Forest Virus (SFV), a mosquito-borne member of the alphaviruses, and host cell proteins. Among the many identified cellular interactors of SFV proteins, the enrichment of factors involved in translation and nonsense-mediated mRNA decay (NMD) was striking, reflecting the virus’ hijacking of the translation machinery and indicating viral countermeasures for escaping NMD by inhibiting NMD at later time points during the infectious cycle. In addition to observing a general inhibition of NMD about 4 hours post infection, we also demonstrate that transient expression of the SFV capsid protein is sufficient to inhibit NMD in cells, suggesting that the massive production of capsid protein during the SFV reproduction cycle is responsible for NMD inhibition.