Dual-Site Phosphorylation of the Control of Virulence Regulator Impacts Group A Streptococcal Global Gene Expression and Pathogenesis

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Group A Streptococcus (GAS) causes a variety of human diseases ranging from mild throat infections to deadly invasive infections. The capacity of GAS to cause infections at such diverse locations is dependent on its ability to precisely control the production of a broad variety of virulence factors. The control of virulence regulator (CovR) is a master regulator of GAS genes encoding virulence factors. It is known that CovR can be phosphorylated on aspartate-53 in vitro and that such phosphorylation increases its regulatory activity, but what additional factors influence CovR-mediated gene expression have not been established. Herein we show for the first time that CovR is phosphorylated in vivo and that phosphorylation of CovR on threonine-65 by the threonine/serine kinase Stk prevents aspartate-53 phosphorylation, thereby decreasing CovR regulatory activity. Further, while CovR-mediated gene repression is highly dependent on aspartate-53 phosphorylation, CovR-mediated gene activation proceeds via a phosphorylation-independent mechanism. Modifications in CovR phosphorylation sites significantly affected the expression of GAS virulence factors during infection and markedly altered the ability of GAS to cause disease in mice. These data establish that multiple inter-related pathways converge to influence CovR phosphorylation, thereby providing new insight into the complex regulatory network used by GAS during infection.

Vyšlo v časopise: Dual-Site Phosphorylation of the Control of Virulence Regulator Impacts Group A Streptococcal Global Gene Expression and Pathogenesis. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004088
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004088

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