The Streptococcus pyogenes orphan protein tyrosine phosphatase, SP-PTP, possesses dual specificity and essential virulence regulatory functions.
Group A Streptococcus (GAS) is a human pathogen that causes high morbidity and mortality. GAS lacks a gene encoding tyrosine kinase but contains one encoding tyrosine phosphatase (SP-PTP). Thus, GAS is thought to lack tyrosine phosphorylation, and the physiological significance of SP-PTP is, therefore, questionable. Here, we demonstrate that SP-PTP possesses dual phosphatase specificity for Tyr- and Ser/Thr-phosphorylated GAS proteins, such as Ser/Thr kinase (SP-STK) and the SP-STK-phosphorylated CovR and WalR proteins. Phenotypic analysis of GAS mutants lacking SP-PTP revealed that the phosphatase activity per se positively regulates growth, cell division and the ability to adhere to and invade host cells. Furthermore, A549 human lung cells infected with GAS mutants lacking SP-PTP displayed increased Ser-/Thr-/Tyr-phosphorylation. SP-PTP also differentially regulates the expression of ∼50% of the total GAS genes, including several virulence genes potentially through the two-component regulators, CovR, WalR and PTS/HPr regulation of Mga. Although these mutants exhibit attenuated virulence, a GAS mutant overexpressing SP-PTP is hypervirulent. Our study provides the first definitive evidence for the presence and importance of Tyr-phosphorylation in GAS and the relevance of SP-PTP as an important therapeutic target.
Department of Pathology, The Ohio State University College of Medicine, Wexner Medical Center, Columbus, OH, USA.
Sashi
S
Kant
Department of Pathology, The Ohio State University College of Medicine, Wexner Medical Center, Columbus, OH, USA.
Shivani
S
Agarwal
Department of Pathology, The Ohio State University College of Medicine, Wexner Medical Center, Columbus, OH, USA.
Preeti
P
Pancholi
Department of Pathology, The Ohio State University College of Medicine, Wexner Medical Center, Columbus, OH, USA.
Vijay
V
Pancholi
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013290:Streptococcal Infections / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000201:enzymology* / Q000235:genetics* / Q000254:growth & development / Q000502:physiology; D016019:Survival Analysis; D014774:Virulence; D037521:Virulence Factors / Q000096:biosynthesis*
D037521:Virulence Factors; D017027:Protein Tyrosine Phosphatases