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

2017 ◽  
Author(s):  
Mandy Muller ◽  
Britt A. Glaunsinger
Keyword(s):  
Gene Expression ◽  
Messenger Rna ◽  
Rna Binding ◽  
Regulatory Element ◽  
Mrna Degradation ◽  
Host Gene ◽  
Host Gene Expression ◽  
Kshv Infection ◽  
Ribonucleoprotein Complexes ◽  
Rna Elements

ABSTRACTDuring lytic Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, the viral endonu-clease 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.AUTHOR SUMMARYThe ability of viruses to control the host gene expression environment is crucial to promote viral infection. Many viruses express factors that reduce host gene expression through widespread mRNA decay. However, some mRNAs escape this fate, like the transcript encoding the immunoregulatory cytokine IL-6 during KSHV infection. IL-6 escape relies on an RNA regulatory element located in its 3’UTR and involves the recruitment of a protective protein complex. Here, we show that this escape extends beyond KSHV to a variety of related and unrelated viral endonucleases. However, the IL-6 element does not protect against cellular endonucleases, revealing for the first time a virus-specific nuclease escape element. We identified a related escape element in the GADD45B mRNA, which displays several similarities with the IL-6 element. However, these elements assemble a largely distinct complex of proteins, leading to differences in the breadth of their protective capacity. Collectively, these findings reveal how a putative new class of RNA elements function to control RNA fate in the background of widespread mRNA degradation by viral endonucleases.

SARS coronavirus protein nsp1 disrupts localization of Nup93 from the nuclear pore complex

2019 ◽  
Vol 97 (6) ◽  
pp. 758-766 ◽  
Author(s):  
Garret N. Gomez ◽  
Fareeha Abrar ◽  
Maya P. Dodhia ◽  
Fabiola G. Gonzalez ◽  
Anita Nag
Keyword(s):  
Gene Expression ◽  
Nuclear Pore Complex ◽  
Rna Binding ◽  
Nonstructural Protein ◽  
Nuclear Lamina ◽  
Host Gene ◽  
Nuclear Pore ◽  
Host Gene Expression ◽  
Nonstructural Protein 1 ◽  
Cytoplasmic Transport

Severe acute respiratory syndrome coronavirus nonstructural protein 1 (nsp1) is a key factor in virus-induced down-regulation of host gene expression. In infected cells, nsp1 engages in a multipronged mechanism to inhibit host gene expression by binding to the 40S ribosome to block the assembly of translationally competent ribosome, and then inducing endonucleolytic cleavage and the degradation of host mRNAs. Here, we report a previously undetected mechanism by which nsp1 exploits the nuclear pore complex and disrupts the nuclear–cytoplasmic transport of biomolecules. We identified members of the nuclear pore complex from the nsp1-associated protein assembly and found that the expression of nsp1 in HEK cells disrupts Nup93 localization around the nuclear envelope without triggering proteolytic degradation, while the nuclear lamina remains unperturbed. Consistent with its role in host shutoff, nsp1 alters the nuclear–cytoplasmic distribution of an RNA binding protein, nucleolin. Our results suggest that nsp1, alone, can regulate multiple steps of gene expression including nuclear–cytoplasmic transport.

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 Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression

2021 ◽  
Vol 7 (6) ◽  
pp. eabe7386 ◽  
Author(s):  
Ke Zhang ◽  
Lisa Miorin ◽  
Tadashi Makio ◽  
Ishmael Dehghan ◽  
Shengyan Gao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Export ◽  
Messenger Rna ◽  
Mrna Export ◽  
Host Gene ◽  
Nuclear Pore ◽  
Host Gene Expression ◽  
Host Interactions ◽  
Inhibitory Function ◽  
Cellular Mrnas

The ongoing unprecedented severe acute respiratory syndrome caused by the SARS-CoV-2 outbreak worldwide has highlighted the need for understanding viral-host interactions involved in mechanisms of virulence. Here, we show that the virulence factor Nsp1 protein of SARS-CoV-2 interacts with the host messenger RNA (mRNA) export receptor heterodimer NXF1-NXT1, which is responsible for nuclear export of cellular mRNAs. Nsp1 prevents proper binding of NXF1 to mRNA export adaptors and NXF1 docking at the nuclear pore complex. As a result, a significant number of cellular mRNAs are retained in the nucleus during infection. Increased levels of NXF1 rescues the Nsp1-mediated mRNA export block and inhibits SARS-CoV-2 infection. Thus, antagonizing the Nsp1 inhibitory function on mRNA export may represent a strategy to restoring proper antiviral host gene expression in infected cells.

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.

scholarly journals Publisher Correction: Exogenously overexpressed intronic long noncoding RNAs activate host gene expression by affecting histone modification in Arabidopsis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhang-Wei Liu ◽  
Nan Zhao ◽  
Yin-Na Su ◽  
Shan-Shan Chen ◽  
Xin-Jian He
Keyword(s):  
Gene Expression ◽  
Histone Modification ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Host Gene ◽  
Host Gene Expression

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Regulation of host gene expression during nodule development in soybeans

1990 ◽  
pp. 701-708 ◽  
Author(s):  
C. Sengupta-Gopalan ◽  
E. Estabrook ◽  
H. Gambliel ◽  
W. Nirunsuksiri ◽  
H. Richter
Keyword(s):  
Gene Expression ◽  
Host Gene ◽  
Nodule Development ◽  
Host Gene Expression
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