scholarly journals Severe Acute Respiratory Syndrome Coronavirus nsp1 Suppresses Host Gene Expression, Including That of Type I Interferon, in Infected Cells

2008 ◽  
Vol 82 (9) ◽  
pp. 4471-4479 ◽  
Author(s):  
Krishna Narayanan ◽  
Cheng Huang ◽  
Kumari Lokugamage ◽  
Wataru Kamitani ◽  
Tetsuro Ikegami ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Severe Acute Respiratory Syndrome ◽  
Mrna Degradation ◽  
Host Gene ◽  
Host Protein ◽  
Type I ◽  
Host Gene Expression ◽  
Infected Cells ◽  
Host Protein Synthesis

ABSTRACT The severe acute respiratory syndrome coronavirus (SARS-CoV) nsp1 protein has unique biological functions that have not been described in the viral proteins of any RNA viruses; expressed SARS-CoV nsp1 protein has been found to suppress host gene expression by promoting host mRNA degradation and inhibiting translation. We generated an nsp1 mutant (nsp1-mt) that neither promoted host mRNA degradation nor suppressed host protein synthesis in expressing cells. Both a SARS-CoV mutant virus, encoding the nsp1-mt protein (SARS-CoV-mt), and a wild-type virus (SARS-CoV-WT) replicated efficiently and exhibited similar one-step growth kinetics in susceptible cells. Both viruses accumulated similar amounts of virus-specific mRNAs and nsp1 protein in infected cells, whereas the amounts of endogenous host mRNAs were clearly higher in SARS-CoV-mt-infected cells than in SARS-CoV-WT-infected cells, in both the presence and absence of actinomycin D. Further, SARS-CoV-WT replication strongly inhibited host protein synthesis, whereas host protein synthesis inhibition in SARS-CoV-mt-infected cells was not as efficient as in SARS-CoV-WT-infected cells. These data revealed that nsp1 indeed promoted host mRNA degradation and contributed to host protein translation inhibition in infected cells. Notably, SARS-CoV-mt infection, but not SARS-CoV-WT infection, induced high levels of beta interferon (IFN) mRNA accumulation and high titers of type I IFN production. These data demonstrated that SARS-CoV nsp1 suppressed host innate immune functions, including type I IFN expression, in infected cells and suggested that SARS-CoV nsp1 most probably plays a critical role in SARS-CoV virulence.

scholarly journals Suppression of Host Gene Expression by nsp1 Proteins of Group 2 Bat Coronaviruses

2009 ◽  
Vol 83 (10) ◽  
pp. 5282-5288 ◽  
Author(s):  
Yukinobu Tohya ◽  
Krishna Narayanan ◽  
Wataru Kamitani ◽  
Cheng Huang ◽  
Kumari Lokugamage ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type I Interferon ◽  
Mrna Degradation ◽  
Host Gene ◽  
Type I ◽  
Host Gene Expression ◽  
Translation Inhibition ◽  
Inhibitory Activities ◽  
Group 2 ◽  
Translational Suppression

ABSTRACT nsp1 protein of severe acute respiratory syndrome coronavirus (SARS-CoV), a group 2b CoV, suppresses host gene expression by promoting host mRNA degradation and translation inhibition. The present study analyzed the activities of nsp1 proteins from the group 2 bat CoV strains Rm1, 133, and HKU9-1, belonging to groups 2b, 2c, and 2d, respectively. The host mRNA degradation and translational suppression activities of nsp1 of SARS-CoV and Rm1 nsp1 were similar and stronger than the activities of the nsp1 proteins of 133 and HKU9-1. Rm1 nsp1 expression in trans strongly inhibited the induction of type I interferon (IFN-I) and IFN-stimulated genes in cells infected with an IFN-inducing SARS-CoV mutant, while 133 and HKU9-1 nsp1 proteins had relatively moderate IFN-inhibitory activities. The results of our studies suggested a conserved function among nsp1 proteins of SARS-CoV and group 2 bat CoVs.

Modification of protein synthesis initiation factors and the shut-off of host protein synthesis in adenovirus-infected cells

Virology ◽  
1989 ◽  
Vol 168 (1) ◽  
pp. 112-118 ◽  
Author(s):  
Robert P. O'Malley ◽  
Roger F. Duncan ◽  
John W.B. Hershey ◽  
Michael B. Mathews
Keyword(s):  
Protein Synthesis ◽  
Host Protein ◽  
Initiation Factors ◽  
Infected Cells ◽  
Protein Synthesis Initiation ◽  
Host Protein Synthesis

scholarly journals The dynamics of coiled bodies in the nucleus of adenovirus-infected cells.

1996 ◽  
Vol 7 (7) ◽  
pp. 1137-1151 ◽  
Author(s):  
L Rebelo ◽  
F Almeida ◽  
C Ramos ◽  
K Bohmann ◽  
A I Lamond ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Hela Cells ◽  
Host Protein ◽  
Coiled Body ◽  
Adenovirus Infection ◽  
Protein Synthesis Inhibitors ◽  
Coiled Bodies ◽  
Infected Cells ◽  
Host Protein Synthesis ◽  
Small Nuclear Ribonucleoproteins

The coiled body is a specific intranuclear structure of unknown function that is enriched in splicing small nuclear ribonucleoproteins (snRNPs). Because adenoviruses make use of the host cell-splicing machinery and subvert the normal subnuclear organization, we initially decided to investigate the effect of adenovirus infection on the coiled body. The results indicate that adenovirus infection induces the disassembly of coiled bodies and that this effect is probably secondary to the block of host protein synthesis induced by the virus. Furthermore, coiled bodies are shown to be very labile structures, with a half-life of approximately 2 h after treatment of HeLa cells with protein synthesis inhibitors. After blocking of protein synthesis, p80 coilin was detected in numerous microfoci that do not concentrate snRNP. These structures may represent precursor forms of the coiled body, which goes through a rapid cycle of assembly/disassembly in the nucleus and requires ongoing protein synthesis to reassemble.

scholarly journals Lysine 164 is critical for SARS-CoV-2 Nsp1 inhibition of host gene expression

2020 ◽  
Author(s):  
Zhou Shen ◽  
Guangxu Zhang ◽  
Yilin Yang ◽  
Mengxia Li ◽  
Siqi Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nonstructural Protein ◽  
Antiviral Drug ◽  
Ribosomal Subunit ◽  
Virus Production ◽  
Host Gene ◽  
Host Protein ◽  
Renilla Luciferase ◽  
Host Gene Expression ◽  
Nonstructural Protein 1

The emerging pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused social and economic disruption worldwide, infecting over 9.0 million people and killing over 469 000 by 24 June 2020. Unfortunately, no vaccine or antiviral drug that completely eliminates the transmissible disease coronavirus disease 2019 (COVID-19) has been developed to date. Given that coronavirus nonstructural protein 1 (nsp1) is a good target for attenuated vaccines, it is of great significance to explore the detailed characteristics of SARS-CoV-2 nsp1. Here, we first confirmed that SARS-CoV-2 nsp1 had a conserved function similar to that of SARS-CoV nsp1 in inhibiting host-protein synthesis and showed greater inhibition efficiency, as revealed by ribopuromycylation and Renilla luciferase (Rluc) reporter assays. Specifically, bioinformatics and biochemical experiments showed that by interacting with 40S ribosomal subunit, the lysine located at amino acid 164 (K164) was the key residue that enabled SARS-CoV-2 nsp1 to suppress host gene expression. Furthermore, as an inhibitor of host-protein expression, SARS-CoV-2 nsp1 contributed to cell-cycle arrest in G0/G1 phase, which might provide a favourable environment for virus production. Taken together, this research uncovered the detailed mechanism by which SARS-CoV-2 nsp1 K164 inhibited host gene expression, laying the foundation for the development of attenuated vaccines based on nsp1 modification.

scholarly journals Middle East Respiratory Syndrome Coronavirus nsp1 Inhibits Host Gene Expression by Selectively Targeting mRNAs Transcribed in the Nucleus while Sparing mRNAs of Cytoplasmic Origin

2015 ◽  
Vol 89 (21) ◽  
pp. 10970-10981 ◽  
Author(s):  
Kumari G. Lokugamage ◽  
Krishna Narayanan ◽  
Keisuke Nakagawa ◽  
Kaori Terasaki ◽  
Sydney I. Ramirez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Middle East ◽  
Nonstructural Protein ◽  
Mrna Translation ◽  
Mrna Degradation ◽  
Middle East Respiratory Syndrome ◽  
Host Gene ◽  
Host Gene Expression ◽  
Highly Pathogenic ◽  
Nonstructural Protein 1

ABSTRACTThe newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome CoV (SARS-CoV) represent highly pathogenic human CoVs that share a property to inhibit host gene expression at the posttranscriptional level. Similar to the nonstructural protein 1 (nsp1) of SARS-CoV that inhibits host gene expression at the translational level, we report that MERS-CoV nsp1 also exhibits a conserved function to negatively regulate host gene expression by inhibiting host mRNA translation and inducing the degradation of host mRNAs. Furthermore, like SARS-CoV nsp1, the mRNA degradation activity of MERS-CoV nsp1, most probably triggered by its ability to induce an endonucleolytic RNA cleavage, was separable from its translation inhibitory function. Despite these functional similarities, MERS-CoV nsp1 used a strikingly different strategy that selectively targeted translationally competent host mRNAs for inhibition. While SARS-CoV nsp1 is localized exclusively in the cytoplasm and binds to the 40S ribosomal subunit to gain access to translating mRNAs, MERS-CoV nsp1 was distributed in both the nucleus and the cytoplasm and did not bind stably to the 40S subunit, suggesting a distinctly different mode of targeting translating mRNAs. Interestingly, consistent with this notion, MERS-CoV nsp1 selectively targeted mRNAs, which are transcribed in the nucleus and transported to the cytoplasm, for translation inhibition and mRNA degradation but spared exogenous mRNAs introduced directly into the cytoplasm or virus-like mRNAs that originate in the cytoplasm. Collectively, these data point toward a novel viral strategy wherein the cytoplasmic origin of MERS-CoV mRNAs facilitates their escape from the inhibitory effects of MERS-CoV nsp1.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human CoV that emerged in Saudi Arabia in 2012. MERS-CoV has a zoonotic origin and poses a major threat to public health. However, little is known about the viral factors contributing to the high virulence of MERS-CoV. Many animal viruses, including CoVs, encode proteins that interfere with host gene expression, including those involved in antiviral immune responses, and these viral proteins are often major virulence factors. The nonstructural protein 1 (nsp1) of CoVs is one such protein that inhibits host gene expression and is a major virulence factor. This study presents evidence for a strategy used by MERS-CoV nsp1 to inhibit host gene expression that has not been described previously for any viral protein. The present study represents a meaningful step toward a better understanding of the factors and molecular mechanisms governing the virulence and pathogenesis of MERS-CoV.

scholarly journals Baculovirus DNA Replication-Specific Expression Factors Trigger Apoptosis and Shutoff of Host Protein Synthesis during Infection

2009 ◽  
Vol 83 (21) ◽  
pp. 11123-11132 ◽  
Author(s):  
Kimberly L. W. Schultz ◽  
Paul D. Friesen
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Dna Replication ◽  
Host Protein ◽  
Late Gene ◽  
Late Gene Expression ◽  
Specific Expression ◽  
Translational Arrest ◽  
Induced Apoptosis ◽  
Host Protein Synthesis

ABSTRACT Apoptosis is an important antivirus defense. To define the poorly understood pathways by which invertebrates respond to viruses by inducing apoptosis, we have identified replication events that trigger apoptosis in baculovirus-infected cells. We used RNA silencing to ablate factors required for multiplication of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV). Transfection with double-stranded RNA (dsRNA) complementary to the AcMNPV late expression factors (lefs) that are designated as replicative lefs (lef-1, lef-2, lef-3, lef-11, p143, dnapol, and ie-1/ie-0) blocked virus DNA synthesis and late gene expression in permissive Spodoptera frugiperda cells. dsRNAs specific to designated nonreplicative lefs (lef-8, lef-9, p47, and pp31) blocked late gene expression without affecting virus DNA replication. Thus, both classes of lefs functioned during infection as defined. Silencing the replicative lefs prevented AcMNPV-induced apoptosis of Spodoptera cells, whereas silencing the nonreplicative lefs did not. Thus, the activity of replicative lefs or virus DNA replication is sufficient to trigger apoptosis. Confirming this conclusion, AcMNPV-induced apoptosis was suppressed by silencing the replicative lefs in cells from a divergent species, Drosophila melanogaster. Silencing replicative but not nonreplicative lefs also abrogated AcMNPV-induced shutdown of host protein synthesis, suggesting that virus DNA replication triggers inhibition of host biosynthetic processes and that apoptosis and translational arrest are linked. Our findings suggest that baculovirus DNA replication triggers a host cell response similar to the DNA damage response in vertebrates, which causes translational arrest and apoptosis. Pathways for detecting virus invasion and triggering apoptosis may therefore be conserved between insects and mammals.

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