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.     

Host restriction of emerging high-pathogenic bunyaviruses via MOV10 by targeting viral nucleoprotein and blocking ribonucleoprotein assembly

Bunyavirus ribonucleoprotein (RNP) that is assembled by polymerized nucleoproteins (N) coating a viral RNA and associating with a viral polymerase can be both the RNA synthesis machinery and the structural core of virions. Bunyaviral N and RNP thus could be assailable targets for host antiviral defense; however, it remains unclear which and how host factors target N/RNP to restrict bunyaviral infection. By mass spectrometry and protein-interaction analyses, we here show that host protein MOV10 targets the N proteins encoded by a group of emerging high-pathogenic representatives of bunyaviruses including severe fever with thrombocytopenia syndrome virus (SFTSV), one of the most dangerous pathogens listed by World Health Organization, in RNA-independent manner. MOV10 that was further shown to be induced specifically by SFTSV and related bunyaviruses in turn inhibits the bunyaviral replication in infected cells in series of loss/gain-of-function assays. Moreover, animal infection experiments with MOV10 knockdown corroborated the role of MOV10 in restricting SFTSV infection and pathogenicity in vivo. Minigenome assays and additional functional and mechanistic investigations demonstrate that the anti-bunyavirus activity of MOV10 is likely achieved by direct impact on viral RNP machinery but independent of its helicase activity and the cellular interferon pathway. Indeed, by its N-terminus, MOV10 binds to a protruding N-arm domain of N consisting of only 34 amino acids but proving important for N function and blocks N polymerization, N-RNA binding, and N-polymerase interaction, disabling RNP assembly. This study not only advances the understanding of bunyaviral replication and host restriction mechanisms but also presents novel paradigms for both direct antiviral action of MOV10 and host targeting of viral RNP machinery.     

Host deadenylation-dependent mRNA decapping factors are required for a key step in brome mosaic virus RNA replication

The genomes of positive-strand RNA [+RNA] viruses perform two mutually exclusive functions: they act as mRNAs for the translation of viral proteins and as templates for viral replication. A universal key step in the replication of +RNA viruses is the coordinated transition of the RNA genome from the cellular translation machinery to the viral replication complex. While host factors are involved in this step, their nature is largely unknown. By using the ability of the higher eukaryotic +RNA virus brome mosaic virus (BMV) to replicate in yeast, we previously showed that the host Lsm1p protein is required for efficient recruitment of BMV RNA from translation to replication. Here we show that in addition to Lsm1p, all tested components of the Lsm1p-7p/Pat1p/Dhh1p decapping activator complex, which functions in deadenylation-dependent decapping of cellular mRNAs, are required for BMV RNA recruitment for RNA replication. In contrast, other proteins of the decapping machinery, such as Edc1p and Edc2p from the deadenylation-dependent decapping pathway and Upf1p, Upf2p, and Upf3p from the deadenylation-independent decapping pathway, had no significant effects. The dependence of BMV RNA recruitment on the Lsm1p-7p/Pat1p/Dhh1p complex was linked exclusively to the 3' noncoding region of the BMV RNA. Collectively, our results suggest that the Lsm1p-7p/Pat1p/Dhh1p complex that transfers cellular mRNAs from translation to degradation might act as a key regulator in the switch from BMV RNA translation to replication.     

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.     

Systems biology of virus-host signaling network interactions

Viruses have evolved to manipulate the host cell machinery for virus propagation, in part by interfering with the host cellular signaling network. Molecular studies of individual pathways have uncovered many viral host-protein targets; however, it is difficult to predict how viral perturbations will affect the signaling network as a whole. Systems biology approaches rely on multivariate, context-dependent measurements and computational analysis to elucidate how viral infection alters host cell signaling at a network level. Here we describe recent advances in systems analyses of signaling networks in both viral and non-viral biological contexts. These approaches have the potential to uncover virus- mediated changes to host signaling networks, suggest new therapeutic strategies, and assess how cell-to-cell variability affects host responses to infection. We argue that systems approaches will both improve understanding of how individual virus-host protein interactions fit into the progression of viral pathogenesis and help to identify novel therapeutic targets.     

Valosin-containing protein (VCP/p97) is required for poliovirus replication and is involved in cellular protein secretion pathway in poliovirus infection

Poliovirus (PV) modifies membrane-trafficking machinery in host cells for its viral RNA replication. To date, ARF1, ACBD3, BIG1/BIG2, GBF1, RTN3, and PI4KB have been identified as host factors of enterovirus (EV), including PV, involved in membrane traffic. In this study, we performed small interfering RNA (siRNA) screening targeting membrane-trafficking genes for host factors required for PV replication. We identified valosin-containing protein (VCP/p97) as a host factor of PV replication required after viral protein synthesis, and its ATPase activity was essential for PV replication. VCP colocalized with viral proteins 2BC/2C and 3AB/3B in PV-infected cells and showed an interaction with 2BC and 3AB but not with 2C and 3A. Knockdown of VCP did not suppress the replication of coxsackievirus B3 or Aichi virus. A VCP-knockdown-resistant PV mutant had an A4881G (a mutation of E253G in 2C) mutation, which is known as a determinant of a secretion inhibition-negative phenotype. However, knockdown of VCP did not affect the inhibition of cellular protein secretion caused by overexpression of each individual viral protein. These results suggested that VCP is a host factor required for viral RNA replication of PV among membrane-trafficking proteins and provides a novel link between cellular protein secretion and viral RNA replication.     

Viral Sensing of the Subcellular Environment Regulates the Assembly of New Viral Replicase Complexes during the Course of Infection

Replication of plus-stranded RNA [(+)RNA] viruses depends on the availability of coopted host proteins and lipids. But, how could viruses sense the accessibility of cellular resources? An emerging concept based on tombusviruses, small plant viruses, is that viruses might regulate viral replication at several steps depending on what cellular factors are available at a given time point. I discuss the role of phospholipids, sterols, and cellular WW domain proteins and eukaryotic elongation factor 1A (eEF1A) in control of activation of the viral RNA-dependent RNA polymerase (RdRp) and regulation of the assembly of viral replicase complexes (VRCs). These regulatory mechanisms might explain how tombusviruses could adjust the efficiency of RNA replication and new VRC assembly to the limiting resources of the host cells during infections.     

Members of the NF90/NFAR protein group are involved in the life cycle of a positive-strand RNA virus

A major issue of current virology concerns the characterization of cellular proteins that operate as functional components of the viral multiplication process. Here we describe a group of host factors designated as 'NFAR proteins' that are recruited by the replication machinery of bovine viral diarrhea virus, a close relative of the human pathogen hepatitis C virus. The NFAR proteins associate specifically with both the termini of the viral RNA genome involving regulatory elements in the 5' and 3' non-translated regions. Modification of the protein interaction sites in the 3' non-translated region yielded viral RNAs that were replication deficient. Viral replication was also inhibited by RNAi approaches that reduced the concentration of RNA helicase A, a member of the NFAR group, in the host cell's cytoplasm. Further experimental data suggest that NFAR proteins mediate a circular conformation of the viral genome that may be important for the coordination of translation and replication. Because NFAR proteins are presumed components of the antiviral response, we suspect that viral recruitment may also serve to weaken cellular defense mechanisms.     

Mechanisms of enveloped RNA virus budding

To spread infection, enveloped viruses must bud from infected host cells. Recent research indicates that HIV and other enveloped RNA viruses bud by appropriating the cellular machinery that is normally used to create vesicles that bud into late endosomal compartments called multivesicular bodies. This new model of virus budding has many potential implications for cell biology and viral pathogenesis.     

Internal translation initiation of picornaviruses and hepatitis C virus

Picornaviruses and other positive-strand RNA viruses like hepatitis C virus (HCV) enter the cell with a single RNA genome that directly serves as the template for translation. Accordingly, the viral RNA genome needs to recruit the cellular translation machinery for viral protein synthesis. By the use of internal ribosome entry site (IRES) elements in their genomic RNAs, these viruses bypass translation competition with the bulk of capped cellular mRNAs and, moreover, establish the option to largely shut-down cellular protein synthesis. In this review, I discuss the structure and function of viral IRES elements, focusing on the recruitment of the cellular translation machinery by the IRES and on factors that may contribute to viral tissue tropism on the level of translation.     

Viral suppressors of RNA silencing

The infection and replication of viruses in the host induce diverse mechanisms for combating viral infection. One of the best-studied antiviral defence mechanisms is based on RNA silencing. Consistently, several viral suppressors of RNA silencing (VSRs) have been identified from almost all plant virus genera, which are surprisingly diverse within and across kingdoms, exhibiting no obvious sequence similarities. VSRs efficiently inhibit host antiviral responses by interacting with the key components of cellular silencing machinery, often mimicking their normal cellular functions. Recent findings have revealed that the impact of VSRs on endogenous pathways is more complex and profound than had been estimated thus far. This review highlights the current understanding of and new insights into the mechanisms and functions of plant VSRs.