The Experts below are selected from a list of 249 Experts worldwide ranked by ideXlab platform
Hong-bing Shu - One of the best experts on this subject based on the ideXlab platform.
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KAT5 acetylates cGAS to promote innate immune response to DNA Virus.
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Ze-min Song, Heng Lin, Wei Guo, Hong-bing ShuAbstract:The DNA sensor cGMP-AMP synthase (cGAS) senses cytosolic microbial or self DNA to initiate a MITA/STING-dependent innate immune response. cGAS is regulated by various posttranslational modifications at its C-terminal catalytic domain. Whether and how its N-terminal unstructured domain is regulated by posttranslational modifications remain unknown. We identified the acetyltransferase KAT5 as a positive regulator of cGAS-mediated innate immune signaling. Overexpression of KAT5 potentiated viral-DNA–triggered transcription of downstream antiviral genes, whereas a KAT5 deficiency had the opposite effects. Mice with inactivated Kat5 exhibited lower levels of serum cytokines in response to DNA Virus Infection, higher viral titers in the brains, and more susceptibility to DNA-Virus–induced death. Mechanistically, KAT5 catalyzed acetylation of cGAS at multiple lysine residues in its N-terminal domain, which promoted its DNA-binding ability. Our findings suggest that KAT5-mediated cGAS acetylation at its N terminus is important for efficient innate immune response to DNA Virus.
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Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response
Protein & cell, 2020Co-Authors: Hong-bing ShuAbstract:The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosolic DNA derived from microbial pathogens or mis-located cellular DNA. Upon DNA binding, cGAS utilizes GTP and ATP as substrates to synthesize cGAMP, leading to MITA-mediated innate immune response. In this study, we identified the phosphatase PPP6C as a negative regulator of cGAS-mediated innate immune response. PPP6C is constitutively associated with cGAS in un-stimulated cells. DNA Virus Infection causes rapid disassociation of PPP6C from cGAS, resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket. Mutation of this serine residue of cGAS impairs its ability to synthesize cGAMP upon DNA Virus Infection. In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity. PPP6C-deficiency promotes innate immune response to DNA Virus in various cells. Our findings suggest that PPP6C-mediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response, which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of Infection to avoid autoimmune response.
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PCBP1 modulates the innate immune response by facilitating the binding of cGAS to DNA.
Cellular & molecular immunology, 2020Co-Authors: Chen-yang Liao, Cao-qi Lei, Hong-bing ShuAbstract:Cyclic GMP-AMP synthase (cGAS) is a key sensor critical for the recognition of DNA in the cytosol and catalyzes the synthesis of the second messenger cyclic GMP-AMP (cGAMP), which binds to the adapter protein MITA (also known as STING, MPYS, and ERIS) to initiate the innate immune response. How the binding of DNA to and the activation of cGAS are regulated remains poorly understood. Using a biochemical purification approach, we identified poly(rC)-binding protein 1 (PCBP1) as a cGAS-associated protein. PCBP1 was recruited to cGAS in a viral Infection-dependent manner. PCBP1 directly bound to DNA and enhanced cGAS binding to its ligands, which was important for cGAS activation. Consistently, PCBP1 deficiency inhibited cytosolic DNA- and DNA Virus-triggered transcription of downstream effector genes. These findings suggest that PCBP1 plays an important role in the cGAS-mediated innate immune response to DNA Virus Infection by promoting the binding of cGAS to viral DNA.
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CSK promotes innate immune response to DNA Virus by phosphorylating MITA.
Biochemical and biophysical research communications, 2020Co-Authors: Peng Gao, Hong-bing ShuAbstract:Upon detection of viral DNA, the cytoplasmic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) utilizes GTP and ATP as substrates to synthesize the second messenger molecule 2'3'cyclic GMP-AMP (cGAMP), which binds to the ER-associated adaptor protein MITA/STING to signal innate antiviral response to DNA Virus. How the cGAS-MITA pathways are post-translationally regulated is not fully understood. In this study, we identified the tyrosine kinase CSK as a positive regulator of cGAS-MITA mediated innate antiviral response. CSK-deficiency inhibits DNA Virus-triggered induction of downstream antiviral effector genes. Following DNA Virus Infection, CSK phosphorylates MITA at Y240 and Y245, which is important for its activation. These results suggest that CSK plays a role in modulating innate immune response to DNA Virus.
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LSm14A is a processing body-associated sensor of viral nucleic acids that initiates cellular antiviral response in the early phase of viral Infection
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Rui Chen, Qian Zhou, Shuai Wang, Ai-ping Mao, Xiaodong Zhang, Hong-bing ShuAbstract:Recognition of viral nucleic acids by pattern recognition receptors initiates type I IFN induction and innate antiviral immune response. Here we show that LSm14A, a member of the LSm family involved in RNA processing in the processing bodies, binds to synthetic or viral RNA and DNA and mediates IRF3 activation and IFN-β induction. Knockdown of LSm14A inhibits cytosolic RNA- and DNA-trigger type I IFN production and cellular antiviral response. Moreover, LSm14A is essential for early-phase induction of IFN-β after either RNA or DNA Virus Infection. We further found that LSm14A-mediated IFN-β induction requires RIG-I–VISA or MITA after RNA or DNA Virus Infection, respectively, and viral Infection causes translocation of LSm14A to peroxisomes, where RIG-I, VISA, and MITA are located. These findings suggest that LSm14A is a sensor for both viral RNA and DNA and plays an important role in initiating IFN-β induction in the early phase of viral Infection.
Britt A. Glaunsinger - One of the best experts on this subject based on the ideXlab platform.
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Alteration of the Premature tRNA Landscape by GammaherpesVirus Infection.
mBio, 2020Co-Authors: Jessica M. Tucker, Aaron M. Schaller, Ian M. Willis, Britt A. GlaunsingerAbstract:ABSTRACT Transfer RNAs (tRNAs) are transcribed by RNA polymerase III (RNAPIII) and play a central role in decoding our genome, yet their expression and noncanonical function remain understudied. Many DNA tumor Viruses enhance the activity of RNAPIII, yet whether Infection alters tRNA expression is largely unknown. Here, we present the first genome-wide analysis of how viral Infection alters the tRNAome. Using a tRNA-specific sequencing method (DM-tRNA-seq), we find that the murine gammaherpesVirus MHV68 induces global changes in premature tRNA (pre-tRNA) expression, with 14% of tRNA genes upregulated more than 3-fold, indicating that differential tRNA gene induction is a characteristic of DNA Virus Infection. Elevated pre-tRNA expression corresponds to increased RNAPIII occupancy for the subset of tRNA genes tested; additionally, posttranscriptional mechanisms contribute to the accumulation of pre-tRNA species. We find increased abundance of tRNA fragments derived from pre-tRNAs upregulated by viral Infection, suggesting that noncanonical tRNA cleavage is also affected. Furthermore, pre-tRNA accumulation, but not RNAPIII recruitment, requires gammaherpesVirus-induced degradation of host mRNAs by the virally encoded mRNA endonuclease muSOX. We hypothesize that depletion of pre-tRNA maturation or turnover machinery contributes to robust accumulation of full-length pre-tRNAs in infected cells. Collectively, these findings reveal pervasive changes to tRNA expression during DNA Virus Infection and highlight the potential of using Viruses to explore tRNA biology. IMPORTANCE Viral Infection can dramatically change the gene expression landscape of the host cell, yet little is known regarding changes in noncoding gene transcription by RNA polymerase III (RNAPIII). Among these are transfer RNAs (tRNAs), which are fundamental in protein translation, yet whose gene regulatory features remain largely undefined in mammalian cells. Here, we perform the first genome-wide analysis of tRNA expression changes during viral Infection. We show that premature tRNAs accumulate during Infection with the model gammaherpesVirus MHV68 as a consequence of increased transcription, but that transcripts do not undergo canonical maturation into mature tRNAs. These findings underscore how tRNA expression is a highly regulated process, especially during conditions of elevated RNAPIII activity.
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Alteration of the premature tRNA landscape by gammaherpesVirus Infection
2019Co-Authors: Britt A. Glaunsinger, Jessica M. Tucker, Aaron M. Schaller, Ian M. WillisAbstract:Transfer RNAs (tRNAs) are transcribed by RNA polymerase III (RNAPIII) and play a central role in decoding our genome, yet their expression and non-canonical function remain understudied. Many DNA tumor Viruses enhance the activity of RNAPIII, yet whether Infection alters tRNA expression is largely unknown. Here, we present the first genome-wide analysis of how viral Infection alters the tRNAome. Using a tRNA-specific sequencing method (DM-tRNA-seq), we find that the murine gammaherpesVirus MHV68 induces global changes in pre-tRNA expression with 14% of tRNA genes upregulated more than 3-fold, indicating that differential tRNA gene induction is a characteristic of DNA Virus Infection. Elevated pre-tRNA expression corresponds to increased RNAPIII occupancy for the subset of tRNA genes tested; additionally, post-transcriptional mechanisms contribute to the accumulation of pre-tRNA species. We find increased abundance of tRNA fragments derived from pre-tRNAs upregulated by viral Infection, suggesting that non-canonical tRNA cleavage is also affected. Further, pre-tRNA accumulation, but not RNAPIII recruitment, requires gammaherpesVirus-induced degradation of host mRNAs by the virally encoded mRNA endonuclease muSOX. We hypothesize that depletion of pre-tRNA maturation or turnover machinery contributes to robust accumulation of full-length pre-tRNAs in infected cells. Collectively, these findings reveal pervasive changes to tRNA expression during DNA Virus Infection and highlight the potential of using Viruses to explore tRNA biology.
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Host noncoding retrotransposons induced by DNA Viruses: a SINE of Infection?
Journal of virology, 2017Co-Authors: Jessica M. Tucker, Britt A. GlaunsingerAbstract:Our genomes are dominated by repetitive elements. The majority of these elements derive from retrotransposons, which expand throughout the genome through a process of reverse transcription and integration. Short interspersed nuclear elements, or SINEs, are an abundant class of retrotransposons that are transcribed by RNA polymerase III, thus generating exclusively noncoding RNA (ncRNA) that must hijack the machinery required for their transposition. SINE loci are generally transcriptionally repressed in somatic cells but can be robustly induced upon Infection with multiple DNA Viruses. Recent research has focused on the gene expression and signaling events that are modulated by SINE ncRNAs, particularly during gammaherpesVirus Infection. Here, we review the biology of these SINE ncRNAs, explore how DNA Virus Infection may lead to their induction, and describe how novel gene regulatory and immune-related functions of these ncRNAs may impact the viral life cycle.
Jessica M. Tucker - One of the best experts on this subject based on the ideXlab platform.
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Alteration of the Premature tRNA Landscape by GammaherpesVirus Infection.
mBio, 2020Co-Authors: Jessica M. Tucker, Aaron M. Schaller, Ian M. Willis, Britt A. GlaunsingerAbstract:ABSTRACT Transfer RNAs (tRNAs) are transcribed by RNA polymerase III (RNAPIII) and play a central role in decoding our genome, yet their expression and noncanonical function remain understudied. Many DNA tumor Viruses enhance the activity of RNAPIII, yet whether Infection alters tRNA expression is largely unknown. Here, we present the first genome-wide analysis of how viral Infection alters the tRNAome. Using a tRNA-specific sequencing method (DM-tRNA-seq), we find that the murine gammaherpesVirus MHV68 induces global changes in premature tRNA (pre-tRNA) expression, with 14% of tRNA genes upregulated more than 3-fold, indicating that differential tRNA gene induction is a characteristic of DNA Virus Infection. Elevated pre-tRNA expression corresponds to increased RNAPIII occupancy for the subset of tRNA genes tested; additionally, posttranscriptional mechanisms contribute to the accumulation of pre-tRNA species. We find increased abundance of tRNA fragments derived from pre-tRNAs upregulated by viral Infection, suggesting that noncanonical tRNA cleavage is also affected. Furthermore, pre-tRNA accumulation, but not RNAPIII recruitment, requires gammaherpesVirus-induced degradation of host mRNAs by the virally encoded mRNA endonuclease muSOX. We hypothesize that depletion of pre-tRNA maturation or turnover machinery contributes to robust accumulation of full-length pre-tRNAs in infected cells. Collectively, these findings reveal pervasive changes to tRNA expression during DNA Virus Infection and highlight the potential of using Viruses to explore tRNA biology. IMPORTANCE Viral Infection can dramatically change the gene expression landscape of the host cell, yet little is known regarding changes in noncoding gene transcription by RNA polymerase III (RNAPIII). Among these are transfer RNAs (tRNAs), which are fundamental in protein translation, yet whose gene regulatory features remain largely undefined in mammalian cells. Here, we perform the first genome-wide analysis of tRNA expression changes during viral Infection. We show that premature tRNAs accumulate during Infection with the model gammaherpesVirus MHV68 as a consequence of increased transcription, but that transcripts do not undergo canonical maturation into mature tRNAs. These findings underscore how tRNA expression is a highly regulated process, especially during conditions of elevated RNAPIII activity.
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Alteration of the premature tRNA landscape by gammaherpesVirus Infection
2019Co-Authors: Britt A. Glaunsinger, Jessica M. Tucker, Aaron M. Schaller, Ian M. WillisAbstract:Transfer RNAs (tRNAs) are transcribed by RNA polymerase III (RNAPIII) and play a central role in decoding our genome, yet their expression and non-canonical function remain understudied. Many DNA tumor Viruses enhance the activity of RNAPIII, yet whether Infection alters tRNA expression is largely unknown. Here, we present the first genome-wide analysis of how viral Infection alters the tRNAome. Using a tRNA-specific sequencing method (DM-tRNA-seq), we find that the murine gammaherpesVirus MHV68 induces global changes in pre-tRNA expression with 14% of tRNA genes upregulated more than 3-fold, indicating that differential tRNA gene induction is a characteristic of DNA Virus Infection. Elevated pre-tRNA expression corresponds to increased RNAPIII occupancy for the subset of tRNA genes tested; additionally, post-transcriptional mechanisms contribute to the accumulation of pre-tRNA species. We find increased abundance of tRNA fragments derived from pre-tRNAs upregulated by viral Infection, suggesting that non-canonical tRNA cleavage is also affected. Further, pre-tRNA accumulation, but not RNAPIII recruitment, requires gammaherpesVirus-induced degradation of host mRNAs by the virally encoded mRNA endonuclease muSOX. We hypothesize that depletion of pre-tRNA maturation or turnover machinery contributes to robust accumulation of full-length pre-tRNAs in infected cells. Collectively, these findings reveal pervasive changes to tRNA expression during DNA Virus Infection and highlight the potential of using Viruses to explore tRNA biology.
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Host noncoding retrotransposons induced by DNA Viruses: a SINE of Infection?
Journal of virology, 2017Co-Authors: Jessica M. Tucker, Britt A. GlaunsingerAbstract:Our genomes are dominated by repetitive elements. The majority of these elements derive from retrotransposons, which expand throughout the genome through a process of reverse transcription and integration. Short interspersed nuclear elements, or SINEs, are an abundant class of retrotransposons that are transcribed by RNA polymerase III, thus generating exclusively noncoding RNA (ncRNA) that must hijack the machinery required for their transposition. SINE loci are generally transcriptionally repressed in somatic cells but can be robustly induced upon Infection with multiple DNA Viruses. Recent research has focused on the gene expression and signaling events that are modulated by SINE ncRNAs, particularly during gammaherpesVirus Infection. Here, we review the biology of these SINE ncRNAs, explore how DNA Virus Infection may lead to their induction, and describe how novel gene regulatory and immune-related functions of these ncRNAs may impact the viral life cycle.
Alfred W. Bronkhorst - One of the best experts on this subject based on the ideXlab platform.
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The DNA Virus Invertebrate iridescent Virus 6 is a target of the Drosophila RNAi machinery
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Alfred W. Bronkhorst, Koen W. R. Van Cleef, Nicolas Vodovar, İkbal Agah İnce, Hervé Blanc, Just M. Vlak, Maria-carla Saleh, Ronald P. Van RijAbstract:RNA Viruses in insects are targets of an RNA interference (RNAi)-based antiviral immune response, in which viral replication intermediates or viral dsRNA genomes are processed by Dicer-2 (Dcr-2) into viral small interfering RNAs (vsiRNAs). Whether dsDNA Virus Infections are controlled by the RNAi pathway remains to be determined. Here, we analyzed the role of RNAi in DNA Virus Infection using Drosophila melanogaster infected with Invertebrate iridescent Virus 6 (IIV-6) as a model. We show that Dcr-2 and Argonaute-2 mutant flies are more sensitive to Virus Infection, suggesting that vsiRNAs contribute to the control of DNA Virus Infection. Indeed, small RNA sequencing of IIV-6–infected WT and RNAi mutant flies identified abundant vsiRNAs that were produced in a Dcr-2–dependent manner. We observed a highly uneven distribution with strong clustering of vsiRNAs to small defined regions (hotspots) and modest coverage at other regions (coldspots). vsiRNAs mapped in similar proportions to both strands of the viral genome, suggesting that long dsRNA derived from convergent overlapping transcripts serves as a substrate for Dcr-2. In agreement, strand-specific RT-PCR and Northern blot analyses indicated that antisense transcripts are produced during Infection. Moreover, we show that vsiRNAs are functional in silencing reporter constructs carrying fragments of the IIV-6 genome. Together, our data indicate that RNAi provides antiviral defense against dsDNA Viruses in animals. Thus, RNAi is the predominant antiviral defense mechanism in insects that provides protection against all major classes of Viruses.
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The DNA Virus Invertebrate iridescent Virus 6 is a target of the Drosophila RNAi machinery
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Alfred W. Bronkhorst, Koen W. R. Van Cleef, Nicolas Vodovar, İkbal Agah İnce, Hervé Blanc, Just M. Vlak, Maria-carla Saleh, Ronald Van RijAbstract:RNA Viruses in insects are targets of an RNA interference (RNAi)-based antiviral immune response, in which viral replication inter-mediates or viral dsRNA genomes are processed by Dicer-2 (Dcr-2) into viral small interfering RNAs (vsiRNAs). Whether dsDNA Virus Infections are controlled by the RNAi pathway remains to be determined. Here, we analyzed the role of RNAi in DNA Virus Infection using Drosophila melanogaster infected with Invertebrate iridescent Virus 6 (IIV-6) as a model. We show that Dcr-2 and Argo-naute-2 mutant flies are more sensitive to Virus Infection, suggesting that vsiRNAs contribute to the control of DNA Virus Infection. Indeed, small RNA sequencing of IIV-6–infected WT and RNAi mutant flies identified abundant vsiRNAs that were produced in a Dcr-2–dependent manner. We observed a highly uneven distribution with strong clustering of vsiRNAs to small defined regions (hot-spots) and modest coverage at other regions (coldspots). vsiRNAs mapped in similar proportions to both strands of the viral genome, suggesting that long dsRNA derived from convergent overlapping transcripts serves as a substrate for Dcr-2. In agreement, strand-specific RT-PCR and Northern blot analyses indicated that antisense transcripts are produced during Infection. Moreover, we show that vsiRNAs are functional in silencing reporter constructs carrying fragments of the IIV-6 genome. Together, our data indicate that RNAi provides antiviral defense against dsDNA Viruses in animals. Thus, RNAi is the predominant antiviral defense mechanism in insects that provides protection against all major classes of Viruses. insect immunity | Iridoviridae | siRNA | antiviral immunity | small RNA profiling | next-generation sequencing
David M. Knipe - One of the best experts on this subject based on the ideXlab platform.
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Herpes Simplex Virus 1 Manipulates Host Cell Antiviral and Proviral DNA Damage Responses.
mBio, 2021Co-Authors: Max E. Mertens, David M. KnipeAbstract:ABSTRACT Cells activate their DNA damage response (DDR) in response to DNA Virus Infection, including adenoViruses, papillomaViruses, polyomaViruses, and herpesViruses. In this study, we found that the DDR kinase pathways activated in normal human fibroblasts by herpes simplex Virus 1 (HSV-1) input genomic DNA, HSV-1 replicating DNA, and progeny DNA and in uninfected cells treated with etoposide are different. We also found using clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 technology that different host gene products are required for the DDR in uninfected versus infected cells. Individual DDR components can be proviral or antiviral in that ataxia-telangiectasia mutated (ATM) and p53 promote and Mre11 restricts replication of ICP0-null HSV-1, but ICP0 expression eliminates these DDR effects. Thus, in total, these results argue that HSV-1 manipulates the host cell DDR to utilize specific components for its optimal replication while inactivating the antiviral aspects of the DDR. IMPORTANCE We investigated the relationship between the DNA damage response, a collection of vital cellular pathways that repair potentially lethal damage to the genome, and the DNA Virus herpes simplex Virus 1. We found that Infection by the Virus triggers the DNA damage response, and key proteins that mediate this response have opposing effects on the replication and production of progeny Viruses. Our work provides novel insights into the relationship between DNA Virus Infection and the cellular response to the viral genome. We speculate that viral gene products modulate this response, providing potentially novel targets for therapeutic intervention against the Virus.
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tripartite motif 22 trim22 protein restricts herpes simplex Virus 1 by epigenetic silencing of viral immediate early genes
PLOS Pathogens, 2021Co-Authors: Tejaswini S Reddi, Philipp Merkl, Soyon Lim, Norman L Letvin, David M. KnipeAbstract:Intrinsic resistance is a crucial line of defense against Virus Infections, and members of the Tripartite Ring Interaction Motif (TRIM) family of proteins are major players in this system, such as cytoplasmic TRIM5α or nuclear promyelocytic leukemia (PML/TRIM19) protein. Previous reports on the antiviral function of another TRIM protein, TRIM22, emphasized its innate immune role as a Type I and Type II interferon-stimulated gene against RNA Viruses. This study shows that TRIM22 has an additional intrinsic role against DNA Viruses. Here, we report that TRIM22 is a novel restriction factor of HSV-1 and limits ICP0-null Virus replication by increasing histone occupancy and heterochromatin, thereby reducing immediate-early viral gene expression. The corresponding wild-type equivalent of the Virus evades the TRIM22-specific restriction by a mechanism independent of ICP0-mediated degradation. We also demonstrate that TRIM22 inhibits other DNA Viruses, including representative members of the β- and γ- herpesViruses. Allelic variants in TRIM22 showed different degrees of anti-herpesviral activity; thus, TRIM22 genetic variability may contribute to the varying susceptibility to HSV-1 Infection in humans. Collectively, these results argue that TRIM22 is a novel restriction factor and expand the list of restriction factors functioning in the infected cell nucleus to counter DNA Virus Infection.