2.
Jauregui AR, Savalia D, Lowry VK, Farrell CM, Wathelet MG.
PLoS One. 2013 Apr 29;8(4):e62416. doi: 10.1371/journal.pone.0062416. Print 2013.
PLoS One. 2013 Apr 29;8(4):e62416. doi: 10.1371/journal.pone.0062416. Print 2013.
Identification of residues of SARS-CoV nsp1 that differentially affect inhibition of gene expression and antiviral signaling.
An epidemic of Severe Acute Respiratory Syndrome (SARS) led to the identification of an associated coronavirus,
SARS-CoV. This virus evades the host innate immune response in part
through the expression of its non-structural protein (nsp) 1, which
inhibits both host gene expression and virus- and interferon
(IFN)-dependent signaling.
Thus, nsp1 is a promising target for drugs, as inhibition of nsp1 would make SARS-CoV more susceptible to the host antiviral defenses. To gain a better understanding of nsp1 mode of action, we generated and analyzed 38 mutants of the SARS-CoV nsp1, targeting 62 solvent exposed residues out of the 180 amino acid protein. From this work, we identified six classes of mutants that abolished, attenuated or increased nsp1 inhibition of host gene expression and/or antiviral signaling. Each class of mutants clustered on SARS-CoV nsp1 surface and suggested nsp1 interacts with distinct host factors to exert its inhibitory activities
Identification of the nsp1 residues critical for its activities and the pathways involved in these activities should help in the design of drugs targeting nsp1. Significantly, several point mutants increased the inhibitory activity of nsp1, suggesting that coronaviruses could evolve a greater ability to evade the host response through mutations of such residues.
Thus, nsp1 is a promising target for drugs, as inhibition of nsp1 would make SARS-CoV more susceptible to the host antiviral defenses. To gain a better understanding of nsp1 mode of action, we generated and analyzed 38 mutants of the SARS-CoV nsp1, targeting 62 solvent exposed residues out of the 180 amino acid protein. From this work, we identified six classes of mutants that abolished, attenuated or increased nsp1 inhibition of host gene expression and/or antiviral signaling. Each class of mutants clustered on SARS-CoV nsp1 surface and suggested nsp1 interacts with distinct host factors to exert its inhibitory activities
Identification of the nsp1 residues critical for its activities and the pathways involved in these activities should help in the design of drugs targeting nsp1. Significantly, several point mutants increased the inhibitory activity of nsp1, suggesting that coronaviruses could evolve a greater ability to evade the host response through mutations of such residues.
- PMID:
- 23658627
- PMCID:
- PMC3639174
- DOI:
- 10.1371/journal.pone.0062416
- [Indexed for MEDLINE]
3.
Huang C, Lokugamage KG, Rozovics JM, Narayanan K, Semler BL, Makino S.
PLoS Pathog. 2011 Dec;7(12):e1002433. doi: 10.1371/journal.ppat.1002433. Epub 2011 Dec 8.
SARS coronavirus
(SCoV) nonstructural protein (nsp) 1, a potent inhibitor of host gene
expression, possesses a unique mode of action: it binds to 40S ribosomes
to inactivate their translation functions and induces host mRNA
degradation. Our previous study demonstrated that nsp1 induces RNA
modification near the 5'-end of a reporter mRNA having a short 5'
untranslated region and RNA cleavage in the encephalomyocarditis virus
internal ribosome entry site (IRES) region of a dicistronic RNA
template, but not in those IRES elements from hepatitis C or cricket
paralysis viruses. By using primarily cell-free, in vitro translation
systems, the present study revealed that the nsp1 induced
endonucleolytic RNA cleavage mainly near the 5' untranslated region of
capped mRNA templates. Experiments using dicistronic mRNAs carrying
different IRESes showed that nsp1 induced endonucleolytic RNA cleavage
within the ribosome loading region of type I and type II picornavirus
IRES elements, but not that of classical swine fever virus IRES, which
is characterized as a hepatitis C virus-like IRES. The nsp1-induced RNA
cleavage of template mRNAs exhibited no apparent preference for a
specific nucleotide sequence at the RNA cleavage sites. Remarkably, SCoV
mRNAs, which have a 5' cap structure and 3' poly A tail like those of
typical host mRNAs, were not susceptible to nsp1-mediated RNA cleavage
and importantly, the presence of the 5'-end leader sequence protected
the SCoV mRNAs from nsp1-induced endonucleolytic RNA cleavage. The
escape of viral mRNAs from nsp1-induced RNA cleavage may be an important
strategy by which the virus circumvents the action of nsp1 leading to
the efficient accumulation of viral mRNAs and viral proteins during
infection.Free PMC Article
4.
Denison MR, Graham RL, Donaldson EF, Eckerle LD, Baric RS.
RNA Biol. 2011 Mar-Apr;8(2):270-9. Epub 2011 Mar 1. Review.
- PMID:
- 21593585
5.
Wang JM, Wang LF, Shi ZL.
Biochem Biophys Res Commun. 2008 Sep 12;374(1):138-42. doi: 10.1016/j.bbrc.2008.06.129. Epub 2008 Jul 11.
- PMID:
- 18619943
6.
Law AH, Lee DC, Cheung BK, Yim HC, Lau AS.
J Virol. 2007 Jan;81(1):416-22. Epub 2006 Oct 11. Erratum in: J Virol. 2007 Mar;81(5):2537.
- PMID:
- 17035307
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