Abstract
It has been estimated for dengue infection that the global population at risk is 3.5 billion people, which makes dengue an important public health problem. The causative agents of dengue are dengue viruses. For dengue virus replication, the dengue virus NS5 protein is of special importance as it has several enzyme activities important for viral replication. Previous reports of phosphorylation and SUMOylation of dengue NS5 have shown these protein modifications have important consequences for NS5 functions. In this report we identify glutathionylation, another reversible post translation modification that impacts on NS5 enzyme activity. Using dengue virus infected cells we employed specific antibodies and mass spectrometry to identify 3 cysteine residues of NS5 protein as being glutathionylated. Glutathionylation is a post translational protein modification where glutathione is covalently attached to a cysteine residue. We showed glutathionylation occurs on 3 conserved cysteine residues of dengue NS5. Then we generated two flavivirus recombinant full length proteins, dengue NS5 and Zika NS5, to characterize two of the NS5 enzyme activities, namely, guanylyltransferase and RNA-dependent RNA polymerase activities. We show glutathionylation of dengue and Zika NS5 affects enzyme activities of the two flavivirus proteins. The data suggests that glutathionylation is a general feature of the flavivirus NS5 protein and the modification has the potential to modulate several of the NS5 enzyme functions.
Highlights
It has been estimated for dengue infection that there is a population at risk of 3.5 billion people, this makes dengue one of the most important public health problems in most tropical and subtropical countries [1]
The causative agent of dengue, the dengue viruses (DENV) are transmitted to humans by the bite of infected female mosquitoes belonging to the Aedes family, most commonly Aedes aegypti and Aedes albopictus [2]
While all of the non-structural proteins are important for dengue virus replication, the dengue virus nonstructural protein 5 (NS5) protein is of special importance as it has several enzyme activities important for viral replication, namely, guanylyltransferase (GTase), RNA guanine-N7-methyltransferase (N7MTase), nucleoside 2’-O-methyltransferase (2’OMTase) and RNA-dependent RNA polymerase (RdRp) activities [16]
Summary
Editor: Xia Jin, Institut Pasteur of Shanghai Chinese Academy of Sciences, CHINA It has been estimated for dengue infection that the global population at risk is 3.5 billion people, which makes dengue an important public health problem. Using dengue virus infected cells we employed specific antibodies and mass spectrometry to identify 3 cysteine residues of NS5 protein as being glutathionylated. The data suggests that glutathionylation is a general feature of the flavivirus NS5 protein and the modification has the potential to modulate several of the NS5 enzyme functions. While all of the non-structural proteins are important for dengue virus replication, the dengue virus NS5 protein is of special importance as it has several enzyme activities important for viral replication, namely, guanylyltransferase (GTase), RNA guanine-N7-methyltransferase (N7MTase), nucleoside 2’-O-methyltransferase (2’OMTase) and RNA-dependent RNA polymerase (RdRp) activities [16].
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