A Common Strategy for Host RNA Degradation by Divergent Viruses

Gaglia, Marta Maria; Covarrubias, Sergio; Wong, Waichi; Glaunsinger, Britt A.

doi:10.1128/jvi.01230-12

Cited by 129 publications

(202 citation statements)

References 22 publications

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“…This 'host shutoff' phenotype can be triggered through a range of mechanisms that operate at nearly every stage of the gene expression cascade. Viruses whose host shutoff strategies involve the induction of widespread mRNA decay include the alpha and gammaherpesviruses, vaccinia virus (VACV), influenza A virus (IAV), and SARS coronavirus (SCoV) [1][2][3][4][5] In each of the above cases, mRNA degradation is induced via one or more internal endonucleolytic cleavages in the target mRNA or, in the case of VACV, direct removal of the mRNA 5' cap [5][6][7][8][9]. This is invariably followed by exonucleolytic degradation of the cleaved fragment(s) by components of the mammalian RNA decay machinery such as Xrn1 [1,10,11].…”

Section: Introductionmentioning

confidence: 99%

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

Muller

Glaunsinger

2017

Preprint

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During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, the viral endonuclease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3' UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation.

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Section: Introductionmentioning

confidence: 99%

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

Muller

Glaunsinger

2017

Preprint

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“…Productive infection by a-and c-herpesviruses induces a global inhibition of protein synthesis resulting from enhanced mRNA degradation (Gaglia et al, 2012). For the c-herpesviruses, this shutoff is mediated by the viral alkaline exonuclease (AE) (Covarrubias et al, 2009;Glaunsinger & Ganem, 2004;Rowe et al, 2007).…”

mentioning

confidence: 99%

Silencing the shutoff protein of Epstein–Barr virus in productively infected B cells points to (innate) targets for immune evasion

Gent

Gram

Boer

et al. 2015

Journal of General Virology

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During productive infection with Epstein-Barr virus (EBV), a dramatic suppression of cellular protein expression is caused by the viral alkaline exonuclease BGLF5. Among the proteins downregulated by BGLF5 are multiple immune components. Here, we show that shutoff reduces expression of the innate EBV-sensing Toll-like receptor-2 and the lipid antigen-presenting CD1d molecule, thereby identifying these proteins as novel targets of BGLF5. To silence BGLF5 expression in B cells undergoing productive EBV infection, we employed an shRNA approach. Viral replication still occurred in these cells, albeit with reduced late gene expression. Surface levels of a group of proteins, including immunologically relevant molecules such as CD1d and HLA class I and class II, were only partly rescued by depletion of BGLF5, suggesting that additional viral gene products interfere with their expression. Our combined approach thus provides a means to unmask novel EBV (innate) immune evasion strategies that may operate in productively infected B cells.

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“…The ability of viruses to accelerate mRNA decay has been intensively studied with members of the herpesvirus family, which replicate in the nucleus and utilize the transcriptional machinery of the cell (18,19). For alphaherpesviruses, accelerated mRNA turnover is mediated by the endoribonuclease activity of the FEN1-like viral vhs protein (20,21).…”

mentioning

confidence: 99%

The D10 Decapping Enzyme of Vaccinia Virus Contributes to Decay of Cellular and Viral mRNAs and to Virulence in Mice

Liu

Wyatt

Orandle

et al. 2014

J Virol

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bPosttranscriptional mechanisms are important for regulation of cellular and viral gene expression. The presence of the 5= cap structure m 7 G(5=)ppp(5=)Nm is a general feature of mRNAs that provides protection from exoribonuclease digestion and enhances translation. Vaccinia virus and other poxviruses encode enzymes for both cap synthesis and decapping. Decapping is mediated by two related enzymes, D9 and D10, which are synthesized before and after viral DNA replication, respectively. The timing of D10 synthesis correlates better with the shutdown of host gene expression, and deletion of this gene has been shown to cause persistence of host and viral mRNAs in infected cells. Here, we constructed specific mutant viruses in which translation of D10 was prevented by stop codons or activity of D10 was abrogated by catalytic site mutations, without other genomic alterations. Both mutants formed plaques of normal size and replicated to similar extents as the parental virus in monkey epithelial cells and mouse embryonic fibroblasts. The synthesis of viral proteins was slightly delayed, and cellular and viral mRNAs persisted longer in cells infected with the mutants compared to either the parental virus or clonal revertant. Despite the mild effects in vitro, both mutants were more attenuated than the revertants in intranasal and intraperitoneal mouse models, and less infectious virus was recovered from organs. In addition, there was less lung histopathology following intranasal infection with mutant viruses. These data suggest that the D10 decapping enzyme may help restrict antiviral responses by accelerating host mRNA degradation during poxvirus infection. P osttranscriptional mechanisms are important for the regulation of cellular and viral gene expression at the levels of RNA stability and translation. The presence of a 5= cap structure m 7 G(5=)ppp(5=)Nm is a general feature of eukaryotic mRNAs and many viral mRNAs that provides protection from exonuclease digestion and enhances translation (1-6). In eukaryotic cells, mRNA decay begins with shortening of the poly(A) tail and proceeds in either the 5=-to-3= or 3=-to-5= direction. The latter is mediated by the cytoplasmic RNA exosome (7-9) and a scavenger enzyme that degrades the cap (8). In the 5=-to-3= pathway, removal of the cap (10-13) is followed by exoribonuclease Xrn1 digestion (14,15). Enzymes with nudix hydrolase motifs that decap cytoplasmic mRNA are present in Saccharomyces cerevisiae and mammalian cells and are thought to function in mRNA decay (10-13, 16, 17).Degradation of cellular mRNA may be advantageous to viruses by decreasing competition for the translational machinery and by reducing the synthesis of factors that contribute to the innate and adaptive immune responses to infection. The ability of viruses to accelerate mRNA decay has been intensively studied with members of the herpesvirus family, which replicate in the nucleus and utilize the transcriptional machinery of the cell (18, 19). For alphaherpesviruses, accelerated mRNA turnover is mediat...

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A Common Strategy for Host RNA Degradation by Divergent Viruses

Cited by 129 publications

References 22 publications

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

Silencing the shutoff protein of Epstein–Barr virus in productively infected B cells points to (innate) targets for immune evasion

The D10 Decapping Enzyme of Vaccinia Virus Contributes to Decay of Cellular and Viral mRNAs and to Virulence in Mice

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