Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation

Kamitani, Wataru; Narayanan, Krishna; Huang, Cheng; Lokugamage, Kumari G.; Ikegami, Tetsuro; Ito, Naoto; Kubo, Hideyuki; Makino, Shinji

doi:10.1073/pnas.0603144103

Cited by 412 publications

(541 citation statements)

References 41 publications

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“…Consistent with this notion, multiple SARS-CoV proteins have recently been suggested to antagonize various aspects of the host innate immunity, as those reported with ORF3b, ORF6, N, and nsp1 (35,36). We have shown in this study that the PLpro domain of nsp3 also serves as an IFN antagonist.…”

Section: Discussionsupporting

confidence: 89%

“…Three SARS-CoV proteins, ORF3b, ORF6, and nucleocapsid (N), were recently identified as IFN antagonists, based on their ability to inhibit IRF-3 activation (35). SARSCoV nsp1 was also shown to inhibit host IFN responses by inducing the degradation of host mRNAs (36). However, others have reported that infection of mouse hepatitis virus, a closely related type 2 coronavirus, or SARS-CoV does not activate IFN-␤ synthesis in murine fibroblasts nor inhibit its induction by poly(I-C) or Sendai virus (SeV) (37,38).…”

mentioning

confidence: 99%

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Regulation of IRF-3-dependent Innate Immunity by the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus

Devaraj

Wang

Chen

et al. 2007

Journal of Biological Chemistry

375

434

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

Regulation of IRF-3-dependent Innate Immunity by the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus

Devaraj

Wang

Chen

et al. 2007

Journal of Biological Chemistry

375

434

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“…However, it appeared not to affect 28S and 18S rRNAs and b-actin expression. A similar observation has also been reported for severe acute respiratory syndrome coronavirus (SARS-CoV) nsp1 (Huang et al, 2011;Kamitani et al, 2009;Kamitani et al, 2006;Narayanan et al, 2008). Individual expression of SARS-CoV nsp1 resulted in low expression levels, which was due to its ability to promote cellular mRNA degradation, including its own RNA transcripts.…”

Section: Discussionsupporting

confidence: 66%

“…As a counteraction to host innate antiviral responses, viruses have evolved strategies to actively suppress and/or evade the innate immune responses. Some viruses encode proteins that selectively interfere with certain components of the IFN system, whilst others have evolved to target the general host gene expression machinery, resulting in blocking of innate immune responses (Basler et al, 2000;Chen et al, 1999;Foy et al, 2003;Kamitani et al, 2009;Kamitani et al, 2006;Komatsu et al, 2004;Le May et al, 2004;Lokugamage et al, 2012;Wang et al, 2000). Various PRRSV nsps (nsp1a, nsp1b, nsp2 and nsp11) appear to be able to suppress the host innate antiviral function (Fang & Snijder, 2010;Yoo et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Targeted mutations in a highly conserved motif of the nsp1β protein impair the interferon antagonizing activity of porcine reproductive and respiratory syndrome virus

Lǐ

Zhu

Lawson

et al. 2013

Journal of General Virology

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Non-structural protein 1b (nsp1b) of porcine reproductive and respiratory syndrome virus (PRRSV) contains a papain-like cysteine protease (PLPb) domain and has been identified as the main viral protein antagonizing the host innate immune response. In this study, nsp1b was determined to suppress the expression of reporter genes as well as to suppress 'self-expression' in transfected cells, and this activity appeared to be associated with its interferon (IFN) antagonist function. To knock down the effect of nsp1b on IFN activity, a panel of site-specific mutations in nsp1b was analysed. Double mutations K130A/R134A (type 1 PRRSV) or K124A/R128A (type 2 PRRSV) targeting a highly conserved motif of nsp1b, GKYLQRRLQ (in bold), impaired the ability of nsp1b to suppress IFN-b and reporter gene expression, as well as to suppress 'self-expression' in vitro. Subsequently, viable recombinant viruses vSD01-08-K130A/R134A and vSD95-21-K124A/R128A, containing double mutations in the GKYLQRRLQ motif were generated using reverse genetics. In comparison with WT viruses, these nsp1b mutants showed impaired growth ability in infected cells, but the PLPb cleavage function was not directly affected. The expression of selected innate immune genes was determined in vSD95-21-K124A/R128A mutant-infected cells. The results consistently showed that gene expression levels of IFN-a, IFN-b and IFNstimulated gene 15 were upregulated in cells that were infected with the vSD95-21-K124A/ R128A compared with that of WT virus. These data suggest that PRRSV nsp1b may selectively suppress cellular gene expression, including expression of genes involved in the host innate immune function. Modifying the key residues in the highly conserved GKYLQRRLQ motif could attenuate virus growth and improve the cellular innate immune responses.

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“…Nsp1, whose structure was recently characterized by NMR (Almeida et al, 2007), is the first mature viral protein expressed in the host cell cytoplasm (Ziebuhr, 2005) and may be involved with host cell mRNA degradation and counteracting innate immune responses (Kamitani et al, 2006). A deletion in the nsp1 coding sequence in MHV was found to strongly reduce cellular gene expression, while low doses of nsp1 mutant MHV elicited potent cytotoxic T-cell responses (Zust et al, 2007).…”

Section: Vaccines Against Sarsmentioning

confidence: 99%

The search for a structural basis for therapeutic intervention against the SARS coronavirus

2007

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The 2003 outbreak of severe acute respiratory syndrome (SARS), caused by a previously unknown coronavirus called SARS-CoV, had profound social and economic impacts worldwide. Since then, structure-function studies of SARSCoV proteins have provided a wealth of information that increases our understanding of the underlying mechanisms of SARS. While no effective therapy is currently available, considerable efforts have been made to develop vaccines and drugs to prevent SARS-CoV infection. In this review, some of the notable achievements made by SARS structural biology projects worldwide are examined and strategies for therapeutic intervention are discussed based on available SARS-CoV protein structures. To date, 12 structures have been determined by X-ray crystallography or NMR from the 28 proteins encoded by SARS-CoV. One key protein, the SARS-CoV main protease (M pro ), has been the focus of considerable structure-based drug discovery efforts. This article highlights the importance of structural biology and shows that structures for drug design can be rapidly determined in the event of an emerging infectious disease.

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Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression by promoting host mRNA degradation

Cited by 412 publications

References 41 publications

Regulation of IRF-3-dependent Innate Immunity by the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus

Regulation of IRF-3-dependent Innate Immunity by the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus

Targeted mutations in a highly conserved motif of the nsp1β protein impair the interferon antagonizing activity of porcine reproductive and respiratory syndrome virus

The search for a structural basis for therapeutic intervention against the SARS coronavirus

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