Streptococcus pyogenes c-di-AMP Phosphodiesterase, GdpP, Influences SpeB Processing and Virulence

Abstract

Small cyclic nucleotide derivatives are employed as second messengers by both prokaryotes and eukaryotes to regulate diverse cellular processes responding to various signals. In bacteria, c-di-AMP has been discovered most recently, and some Gram-positive pathogens including S. pyogenes use this cyclic nucleotide derivative as a second messenger instead of c-di-GMP, a well-studied important bacterial second messenger. GdpP, c-di-AMP phosphodiesterase, is responsible for degrading c-di-AMP inside cells, and the cellular role of GdpP in S. pyogenes has not been examined yet. To test the cellular role of GdpP, we created a strain with a nonpolar inframe deletion of the gdpP gene, and examined the properties of the strain including virulence. From this study, we demonstrated that GdpP influences the biogenesis of SpeB, the major secreted cysteine protease, at a post-translational level, susceptibility to the beta lactam antibiotic ampicillin, and is necessary for full virulence in a murine subcutaneous infection model.

Streptococcus pyogenes Polymyxin B-Resistant Mutants Display Enhanced ExPortal Integrity

“…Several global regulatory pathways that link metabolic stress to guanine metabolism have been identified, including (p)ppGpp and the stringent response (37) and the transcription regulator CodY (58). Other mutants represent pathways that link other aspects of nucleotide metabolism to general stress responses, including the second messenger cyclic-di-AMP phosphodiesterase GdpP (55,59,60), which has recently been linked to potassium import under osmotic stress (61)(62)(63). If triggering a stress response is a characteristic shared by other mutations in this collection, then it is possible that those involving the loss of function of a single subunit of a multicomponent membrane transporter may cause a membrane perturbation that induces a stress response.…”

“…However, several of the PB-resistant mutants had a defect in SpeB expression associated with mutations in gdpP and clpX. It has previously been reported that inactivation of gdpP is associated with decreased SpeB activity associated with a kinetic delay in processing the SpeB zymogen to its active form (30,59). The recently described second messenger molecule cyclic-di-AMP is the substrate of the GdpP phosphodiesterase and has been linked to regulation of cell wall and cell envelope homeostasis (55,59,(73)(74)(75), suggesting an overlap of these activities with regulation of SpeB expression.…”

“…It has previously been reported that inactivation of gdpP is associated with decreased SpeB activity associated with a kinetic delay in processing the SpeB zymogen to its active form (30,59). The recently described second messenger molecule cyclic-di-AMP is the substrate of the GdpP phosphodiesterase and has been linked to regulation of cell wall and cell envelope homeostasis (55,59,(73)(74)(75), suggesting an overlap of these activities with regulation of SpeB expression. In addition, DarR, a recently identified cyclic-di-AMP-responsive transcription regulator, controls expression of fatty acid biosynthesis genes in Mycobacterium smegmatis (76), consistent with other data implicating regulation of membrane lipid composition, stress response, PB resistance, and ExPortal integrity.…”

Diadenylate cyclase evaluation of ssDacA (SSU98_1483) in Streptococcus suis serotype 2

“…In Bacillus subtilis, bacterial c-di-AMP levels are reduced in response to DNA damage, resulting in delayed sporulation (Oppenheimer-Shaanan et al, 2011). High c-di-AMP levels result in smaller bacterial size in Staphylococcus aureus (Corrigan et al, 2011), c-di-AMP secreted by Listeria monocytogenes triggers a cytosolic pathway for innate immunity (Woodward et al, 2010), and c-di-AMP homeostasis is required for the virulence of Streptococcus pyogenes and Streptococcus pneumonia (Bai et al, 2013;Cho and Kang, 2013;Witte et al, 2013). c-di-AMP is synthesized by a protein containing a diadenylate cyclase domain (DAC domain).…”

DhhP, a Cyclic di-AMP Phosphodiesterase of Borrelia burgdorferi, Is Essential for Cell Growth and Virulence

“…In term of pathogenesis, c-di-AMP has been shown to function as PAMP (pathogen-associated molecular patterns), secreted through the multidrug resistance transporter (MTR) system of L. monocytogenes to the host cytosol, where it triggers STING (stimulator of interferon genes)-mediated activation of the interferon (IFN) response. Inactivation of c-di-AMP PDE genes resulted in reduced infection in several pathogens, including L. monocytogenes, S. pyogenes, and S. pneumoniae (7,8,22,26).…”