Coordinated Destruction of Cellular Messages in Translation Complexes by the Gammaherpesvirus Host Shutoff Factor and the Mammalian Exonuclease Xrn1

Several viruses encode factors that promote host mRNA degradation to silence gene expression. It is unclear, however, whether cellular mRNA turnover pathways are engaged to assist in this process. In Kaposi's sarcoma-associated herpesvirus this phenotype is enacted by the host shutoff factor SOX. Here we show that SOX-induced mRNA turnover is a two-step process, in which mRNAs are first cleaved internally by SOX itself then degraded by the cellular exonuclease Xrn1. SOX therefore bypasses the regulatory steps of deadenylation and decapping normally required for Xrn1 activation. SOX is likely recruited to translating mRNAs, as it cosediments with translation initiation complexes and depletes polysomes. Cleaved mRNA intermediates accumulate in the 40S fraction, indicating that recognition occurs at an early stage of translation. This is the first example of a viral protein commandeering cellular mRNA turnover pathways to destroy host mRNAs, and suggests that Xrn1 is poised to deplete messages undergoing translation in mammalian cells.

• Publication year

  2011

• Venue

  PLoS Pathogens

• Publication date

  2011-10-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.ppat.1002339PMID 22046136PMCID 3203186
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Deep Sequencing Reveals Direct Targets of Gammaherpesvirus-Induced mRNA Decay and Suggests That Multiple Mechanisms Govern Cellular Transcript Escape

  2011cited by this paper
• Crystal structure of a KSHV–SOX–DNA complex: insights into the molecular mechanisms underlying DNase activity and host shutoff

  2011influential reference
• Novel endoribonucleases as central players in various pathways of eukaryotic RNA metabolism.

  2010cited by this paper
• All things must pass: contrasts and commonalities in eukaryotic and bacterial mRNA decay

  2010cited by this paper
• Viruses and the cellular RNA decay machinery

  2010cited by this paper
• mRNA Degradation Plays a Significant Role in the Program of Gene Expression Regulated by Phosphatidylinositol 3-Kinase Signaling

  2010cited by this paper
• The N-Terminal Domain of the Arenavirus L Protein Is an RNA Endonuclease Essential in mRNA Transcription

  2010cited by this paper
• Sindbis virus usurps the cellular HuR protein to stabilize its transcripts and promote productive infections in mammalian and mosquito cells.

  2010cited by this paper
• Human Pat1b Connects Deadenylation with mRNA Decapping and Controls the Assembly of Processing Bodies

  2010cited by this paper
• Multiple mRNA decapping enzymes in mammalian cells.

  2010cited by this paper
• Nuclear Import of Cytoplasmic Poly(A) Binding Protein Restricts Gene Expression via Hyperadenylation and Nuclear Retention of mRNA

  2010cited by this paper
• SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells

  2009influential reference
• A two-pronged strategy to suppress host protein synthesis by SARS coronavirus Nsp1 protein

  2009cited by this paper
• IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates.

  2009cited by this paper
• Aberrant Herpesvirus-Induced Polyadenylation Correlates With Cellular Messenger RNA Destruction

  2009cited by this paper
• The N-terminal PIN domain of the exosome subunit Rrp44 harbors endonuclease activity and tethers Rrp44 to the yeast core exosome

  2009cited by this paper
• Crystal structure of an avian influenza polymerase PAN reveals an endonuclease active site

  2009cited by this paper
• Host Shutoff Is a Conserved Phenotype of Gammaherpesvirus Infection and Is Orchestrated Exclusively from the Cytoplasm

  2009cited by this paper
• Crystal structure of the shutoff and exonuclease protein from the oncogenic Kaposi’s sarcoma‐associated herpesvirus

  2009cited by this paper
• The role of RNAi and microRNAs in animal virus replication and antiviral immunity.

  2009cited by this paper
• A bridge crosses the active-site canyon of the Epstein-Barr virus nuclease with DNase and RNase activities.

  2009cited by this paper
• Concordant Regulation of Translation and mRNA Abundance for Hundreds of Targets of a Human microRNA

  2009cited by this paper
• Endonucleolytic initiation of mRNA decay in Escherichia coli.

  2009cited by this paper
• The virion-packaged endoribonuclease of herpes simplex virus 1 cleaves mRNA in polyribosomes

  2009cited by this paper
• Studies of the 5′ Exonuclease and Endonuclease Activities of CPSF-73 in Histone Pre-mRNA Processing

  2008cited by this paper
• Endonucleolytic RNA cleavage by a eukaryotic exosome

  2008cited by this paper
• The exosome contains domains with specific endoribonuclease, exoribonuclease and cytoplasmic mRNA decay activities

  2008cited by this paper
• A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity.

  2008cited by this paper
• Modulation of enteroviral proteinase cleavage of poly(A)-binding protein (PABP) by conformation and PABP-associated factors.

  2008cited by this paper
• SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan.

  2008influential reference
• Host shutoff during productive Epstein–Barr virus infection is mediated by BGLF5 and may contribute to immune evasion

  2007cited by this paper
• The highways and byways of mRNA decay

  2007cited by this paper
• 5'-to-3' exoribonuclease activity in bacteria: role of RNase J1 in rRNA maturation and 5' stability of mRNA.

  2007cited by this paper
• Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation

  2006cited by this paper
• The Virion Host Shutoff Protein (UL41) of Herpes Simplex Virus 1 Is an Endoribonuclease with a Substrate Specificity Similar to That of RNase A

  2006cited by this paper
• The U(L)41 protein of herpes simplex virus 1 degrades RNA by endonucleolytic cleavage in absence of other cellular or viral proteins.

  2006cited by this paper
• Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation

  2006cited by this paper
• Decay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein Response

  2006cited by this paper
• mRNA Decay during Herpes Simplex Virus (HSV) Infections: Protein-Protein Interactions Involving the HSV Virion Host Shutoff Protein and Translation Factors eIF4H and eIF4A

  2005cited by this paper
• Control of gene expression during T cell activation: alternate regulation of mRNA transcription and mRNA stability

  2005cited by this paper
• The Exonuclease and Host Shutoff Functions of the SOX Protein of Kaposi's Sarcoma-Associated Herpesvirus Are Genetically Separable

  2005cited by this paper
• Lytic KSHV infection inhibits host gene expression by accelerating global mRNA turnover.

  2004cited by this paper
• Highly Selective Escape from KSHV-mediated Host mRNA Shutoff and Its Implications for Viral Pathogenesis

  2004cited by this paper
• Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs.

  2004cited by this paper
• Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in Drosophila

  2004cited by this paper
• Global Changes in Kaposi's Sarcoma-Associated Virus Gene Expression Patterns following Expression of a Tetracycline-Inducible Rta Transactivator

  2003cited by this paper
• The hDcp2 protein is a mammalian mRNA decapping enzyme

  2002cited by this paper
• Global analysis of stress-regulated mRNA turnover by using cDNA arrays

  2002cited by this paper
• Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20.

  2001cited by this paper
• mRNA Decay during Herpesvirus Infections: Interaction between a Putative Viral Nuclease and a Cellular Translation Factor

  2001cited by this paper
• Translational repression by a novel partner of human poly(A) binding protein, Paip2.

  2001cited by this paper
• The Herpes Simplex Virus vhs Protein Induces Endoribonucleolytic Cleavage of Target RNAs in Cell Extracts

  1999cited by this paper
• The DCP2 protein is required for mRNA decapping in Saccharomyces cerevisiae and contains a functional MutT motif

  1999cited by this paper
• The human cytomegalovirus UL98 gene encodes the conserved herpesvirus alkaline nuclease.

  1997cited by this paper
• The virion host shutoff protein of herpes simplex virus type 1: messenger ribonucleolytic activity in vitro

  1996cited by this paper
• mRNA decay mediated by two distinct AU-rich elements from c-fos and granulocyte-macrophage colony-stimulating factor transcripts: different deadenylation kinetics and uncoupling from translation

  1995cited by this paper
• Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease.

  1995cited by this paper
• Autoregulation of poly(A)-binding protein synthesis in vitro.

  1995cited by this paper
• Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.

  1995cited by this paper
• Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs.

  1995cited by this paper
• Deadenylation of the unstable mRNA encoded by the yeast MFA2 gene leads to decapping followed by 5'-->3' digestion of the transcript.

  1994cited by this paper
• Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.

  1994cited by this paper
• A turnover pathway for both stable and unstable mRNAs in yeast: evidence for a requirement for deadenylation.

  1993cited by this paper
• Comparison of exonucleolytic activities of herpes simplex virus type-1 DNA polymerase and DNase.

  1990cited by this paper
• Purification and properties of Epstein-Barr virus DNase expressed in Escherichia coli

  1990cited by this paper
• The characterization of the EBV alkaline deoxyribonuclease cloned and expressed in E. coli.

  1989cited by this paper
• Herpes simplex virus virion host shutoff function

  1988cited by this paper
• The herpes simplex virus virion host shutoff function

  1988cited by this paper
• DNase Induced After Infection of KB Cells by Herpes Simplex Virus Type 1 or Type 2 II. Characterization of an Associated Endonuclease Activity

  1979cited by this paper
• The deoxyribonuclease induced after infection of KB cells by herpes simplex virus type 1 or type 2. I. Purification and characterization of the enzyme.

  1978cited by this paper
• Influence of Ionic Strength, pH, and Chelation of Divalent Metals on Isolation of Polyribosomes from Tobacco Leaves.

  1976cited by this paper
• Importin (cid:1) -Mediated Nuclear Import of Cytoplasmic Poly(A) Binding Protein Occurs as a Direct Consequence of Cytoplasmic mRNA Depletion (cid:1)

  year unknowncited by this paper

• Coronavirus endoribonuclease nsp15 suppresses host protein synthesis and evades PKR-eIF2α-mediated translation shutoff to ensure viral protein synthesis

  2025cites this paper
• Gammaherpesvirus infection triggers the formation of tRNA fragments from premature tRNAs

  2025influential citation
• Epstein-Barr virus induces host shutoff extensively via BGLF5-independent mechanisms

  2024cites this paper
• Gammaherpesvirus infection triggers the formation of tRNA fragments from premature tRNAs

  2024cites this paper
• WITHDRAWN: Gammaherpesvirus infection alters transfer RNA splicing and triggers tRNA cleavage

  2024cites this paper
• Mechanisms and consequences of mRNA destabilization during viral infections

  2024influential citation
• Translational arrest and mRNA decay are independent activities of alphaherpesvirus virion host shutoff proteins

  2024cites this paper
• Interferon induced circRNAs escape herpesvirus host shutoff and suppress lytic infection

  2024influential citation
• EBV Reactivation from Latency Is a Degrading Experience for the Host

  2023influential citation
• Interferon induced circRNAs escape herpesvirus host shutoff and suppress lytic infection

  2023cites this paper
• The Role of Viral RNA Degrading Factors in Shutoff of Host Gene Expression.

  2022cites this paper
• Herpes Simplex Virus 1 Expressing GFP-Tagged Virion Host Shutoff (vhs) Protein Uncouples the Activities of RNA Degradation and Differential Nuclear Retention of the Virus Transcriptome

  2022cites this paper
• Shiftless, a Critical Piece of the Innate Immune Response to Viral Infection

  2022cites this paper
• Herpes simplex virus 1 expressing GFP-tagged virion host shutoff (vhs) protein uncouples the activities of degradation and nuclear retention of the infected cell transcriptome

  2022cites this paper
• DNA processing by the Kaposi's sarcoma-associated herpesvirus alkaline exonuclease SOX contributes to viral gene expression and infectious virion production

  2022cites this paper
• Shiftless Restricts Viral Gene Expression and Influences RNA Granule Formation during KSHV lytic replication

  2022cites this paper
• Shiftless Restricts Viral Gene Expression and Influences RNA Granule Formation during Kaposi’s Sarcoma-Associated Herpesvirus Lytic Replication

  2022cites this paper
• Inhibition of Host Gene Expression by KSHV: Sabotaging mRNA Stability and Nuclear Export

  2021cites this paper
• Feline Calicivirus Proteinase-Polymerase Protein Degrades mRNAs To Inhibit Host Gene Expression

  2021cites this paper
• The m6A reader YTHDC2 is essential for escape from KSHV SOX-induced RNA decay

  2021cites this paper
• Fated for decay: RNA elements targeted by viral endonucleases

  2020cites this paper
• The SHAPE of U: Mapping Out Protective Elements in mRNA Escapees

  2020cites this paper
• Human Pumilio proteins directly bind the CCR4-NOT deadenylase complex to regulate the transcriptome

  2020cites this paper
• Feline calicivirus strain 2280 p30 antagonizes type I interferon-mediated antiviral innate immunity through directly degrading IFNAR1 mRNA

  2020cites this paper
• Stealing the Show: KSHV Hijacks Host RNA Regulatory Pathways to Promote Infection

  2020cites this paper
• Redefining De Novo Gammaherpesvirus Infection Through High-Dimensional, Single-Cell Analysis of Virus and Host

  2020cites this paper
• Host shutoff activity of VHS and SOX-like proteins: role in viral survival and immune evasion

  2020cites this paper
• Fine-tuning a blunt tool: Regulation of viral host shutoff RNases

  2020cites this paper
• Biochemical Characterization of Yeast Xrn1.

  2020cites this paper
• KSHV lytic mRNA is efficiently translated in the absence of eIF 4 F 1

  2020cites this paper
• RNA decay during gammaherpesvirus infection reduces RNA polymerase II occupancy of host promoters but spares viral promoters

  2020cites this paper
• INTEGRATING VIROLOGY AND PROTEOMICS TO COMPREHEND MECHANISMS OF INNATE IMMUNE SIGNALING DURING HERPESVIRUS INFECTION

  2019cites this paper
• Feedback to the central dogma: cytoplasmic mRNA decay and transcription are interdependent processes

  2019cites this paper
• Xrn1 activity broadly represses RNA polymerase II occupancy at mammalian but not viral promoters during herpesvirus infection

  2019cites this paper
• Herpesvirus infection reduces Pol II occupancy of host promoters but spares viral promoters

  2019cites this paper
• C19ORF66 Broadly Escapes Virus-Induced Endonuclease Cleavage and Restricts Kaposi’s Sarcoma-Associated Herpesvirus

  2019cites this paper
• The Interplay between the RNA Decay and Translation Machinery in Eukaryotes.

  2018cites this paper
• African Swine Fever Virus Biology and Vaccine Approaches.

  2018cites this paper
• C19ORF66 broadly escapes viral-induced endonuclease cleavage and restricts Kaposi’s Sarcoma Associated Herpesvirus (KSHV)

  2018cites this paper
• KSHV requires eIF3d for cholesterol biosynthesis to support lytic replication

  2018cites this paper
• The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression

  2018cites this paper
• Changes in mRNA abundance drive shuttling of RNA binding proteins, linking cytoplasmic RNA degradation to transcription

  2018influential citation
• Viral manipulation of host mRNA decay.

  2018cites this paper
• Viral-Mediated mRNA Degradation for Pathogenesis

  2018influential citation
• Site specific target binding controls RNA cleavage efficiency by the Kaposi's sarcoma-associated herpesvirus endonuclease SOX

  2018influential citation
• Kaposi's Sarcoma-Associated Herpesvirus mRNA Accumulation in Nuclear Foci Is Influenced by Viral DNA Replication and Viral Noncoding Polyadenylated Nuclear RNA

  2018cites this paper
• Characterization of the African Swine Fever Virus Decapping Enzyme during Infection

  2017cites this paper
• Viral and Cellular N6-Methyladenosine (m6A) and N6, 2′-O-Dimethyladenosine (m6Am) Epitranscriptomes in KSHV Life Cycle

  2017cites this paper
• The Battle of RNA Synthesis: Virus versus Host

  2017cites this paper
• Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

  2017influential citation
• KSHV SOX mediated host shutoff: the molecular mechanism underlying mRNA transcript processing

  2017influential citation
• Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication

  2017cites this paper
• Nuclease escape elements protect messenger RNA against cleavage by 1 multiple viral endonucleases 2 3

  2017influential citation
• Nuclease escape elements protect messenger RNA against cleavage by 1 multiple viral endonucleases 2

  2017influential citation
• Shutoff of Host Gene Expression in Influenza A Virus and Herpesviruses: Similar Mechanisms and Common Themes

  2016influential citation
• A Tale of Two RNAs during Viral Infection: How Viruses Antagonize mRNAs and Small Non-Coding RNAs in The Host Cell

  2016cites this paper
• Next-Generation Sequencing in the Understanding of Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) Biology

  2016cites this paper
• Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

  2016cites this paper
• The KSHV RNA regulator ORF57: target specificity and its role in the viral life cycle

  2016cites this paper
• Rôle de la protéine EB2 du virus d'Epstein-Barr dans le métabolisme des ARN messagers

  2016influential citation
• Selective Degradation of Host RNA Polymerase II Transcripts by Influenza A Virus PA-X Host Shutoff Protein

  2016cites this paper
• Utilising omics approaches to understand Kaposi's sarcoma-associated herpesvirus

  2015influential citation
• Viral-induced global mRNA degradation influences viral mRNA abundance and host transcription rates

  2015influential citation
• Title Transcriptome-Wide Cleavage Site Mapping on Cellular mRNAs Reveals Features Underlying Sequence-Specific Cleavage by the Viral Ribonuclease SOX Permalink

  2015influential citation
• Cellular 5′-3′ mRNA Exonuclease Xrn1 Controls Double-Stranded RNA Accumulation and Anti-Viral Responses

  2015cites this paper
• Timing Is Everything: Coordinated Control of Host Shutoff by Influenza A Virus NS1 and PA-X Proteins

  2015cites this paper
• Ribosome Profiling as a Tool to Decipher Viral Complexity.

  2015cites this paper
• Emerging roles for RNA degradation in viral replication and antiviral defense

  2015cites this paper
• Do You Believe in ReincaRNAtion? Herpesviruses Reveal Connection between RNA Decay and Synthesis.

  2015cites this paper
• Geminivirus Activates ASYMMETRIC LEAVES 2 to Accelerate Cytoplasmic DCP2-Mediated mRNA Turnover and Weakens RNA Silencing in Arabidopsis

  2015cites this paper
• Transcriptome-Wide Cleavage Site Mapping on Cellular mRNAs Reveals Features Underlying Sequence-Specific Cleavage by the Viral Ribonuclease SOX

  2015cites this paper
• A Ribonucleoprotein Complex Protects the Interleukin-6 mRNA from Degradation by Distinct Herpesviral Endonucleases

  2015cites this paper
• Viral Nucleases Induce an mRNA Degradation-Transcription Feedback Loop in Mammalian Cells

  2015cites this paper
• A shutoff and exonuclease mutant of murine gammaherpesvirus-68 yields infectious virus and causes RNA loss in type I interferon receptor knockout cells.

  2014cites this paper
• Gammaherpesviral Gene Expression and Virion Composition Are Broadly Controlled by Accelerated mRNA Degradation

  2014cites this paper
• Noncoding Subgenomic Flavivirus RNA: Multiple Functions in West Nile Virus Pathogenesis and Modulation of Host Responses

  2014cites this paper
• KSHV 2.0: A Comprehensive Annotation of the Kaposi's Sarcoma-Associated Herpesvirus Genome Using Next-Generation Sequencing Reveals Novel Genomic and Functional Features

  2014cites this paper
• Nuclear Translocation and Regulation of Intranuclear Distribution of Cytoplasmic Poly(A)-Binding Protein Are Distinct Processes Mediated by Two Epstein Barr Virus Proteins

  2014influential citation
• The chromatin modification by SUMO-2/3 but not SUMO-1 prevents the epigenetic activation of key immune-related genes during Kaposi’s sarcoma associated herpesvirus reactivation

  2013cites this paper
• Diversion of stress granules and P-bodies during viral infection

  2013influential citation
• Mitochondrial Nucleases ENDOG and EXOG Participate in Mitochondrial DNA Depletion Initiated by Herpes Simplex Virus 1 UL12.5

  2013cites this paper
• Dual Upstream Open Reading Frames Control Translation of a Herpesviral Polycistronic mRNA By

  2013cites this paper
• Dual Short Upstream Open Reading Frames Control Translation of a Herpesviral Polycistronic mRNA

  2013cites this paper
• Manipulation of Cellular Processing Bodies and Their Constituents by Viruses

  2013cites this paper
• African swine fever virus controls the host transcription and cellular machinery of protein synthesis.

  2013cites this paper
• An RNA Element in Human Interleukin 6 Confers Escape from Degradation by the Gammaherpesvirus SOX Protein

  2013cites this paper
• Tinkering with translation: protein synthesis in virus-infected cells.

  2013cites this paper
• Virus‐encoded endonucleases: expected and novel functions

  2013cites this paper
• Interplay between viruses and host mRNA degradation

  2012cites this paper
• The “Bridge” in the Epstein-Barr Virus Alkaline Exonuclease Protein BGLF5 Contributes to Shutoff Activity during Productive Infection

  2012cites this paper
• Diverse virus-host interactions influence RNA-based regulation during γ-herpesvirus infection.

  2012cites this paper
• eview frican swine fever virus controls the host transcription and cellular machinery f protein synthesis

  2012cites this paper
• Tracking expression and subcellular localization of RNA and protein species using high-throughput single cell imaging flow cytometry.

  2012cites this paper
• The Nuclear Functions of Host Cytoplasmic Poly(A) Binding Protein during Viral Infection

  2012cites this paper
• Characterising the role of murine gammaherpesvirus-68 host shutoff protein in mediating cellular mRNA degradation

  2012influential citation
• A Common Strategy for Host RNA Degradation by Divergent Viruses

  2012cites this paper
• Characterizing the Molecular Basis for mRNA Targeting and Destruction by the Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Protein SOX

  2012cites this paper