Mechanisms of Saers Two-Component System Regulating Secretion Stress Responses in Staphylococcus Aureus

Most bacterial secretory proteins are transported across the membrane in an unfolded state. After membrane translocation, the proteins need to be folded into its correct conformation and become functionally active and then secreted into external environment. The misfolded or unfolded proteins are unstable and will elicit secretion stress responses to trigger signaling of two component system (TCS) to activate the expression of the quality control (QC) proteases, which is responsible for degrading the aberrant proteins. The process, called quality control of protein secretion, is regulated by foldase, TCS and QC proteases. Staphylococcus aureus is an important community and nosocomial-associated pathogen, which produces and exports many virulence factors to cause human diseases. So far, little is known about the mechanisms of quality control of protein secretion in S. aureus. Our quantitative proteomic analysis revealed that deletion of prsA, which encodes a membrane-bound foldase PrsA, altered the exoproteome of S. aureus, suggesting that PrsA is involved in quality control of protein secretion. The results of the proteomic analysis also demonstrated that deletion in prsA decreased the amount and stability of protein A (SpA), a major virulent factor secreted by S. aureus. Furthermore, our DNA microarray analysis showed that prsA deletion activated the expression of SaeRS TCS. Base on the preliminary results, this study hypothesizes that deletion in prsA results in the accumulations of misfolded proteins in the membrane-cell wall interface and elicits secretion stress responses, which will trigger signaling of SaeRS TCS to activate the expression of QC protease for degrading the unfolded or misfolded proteins. Therefore, the objective of this proposal is to investigate the mechanisms underlying quality control of proteins secretion regulated by SaeRS TCS. The specific aims of this study include: (1) Investigating the regulatory responses of SaeRS TCS to secretion stress and influences on secretion and functions of protein A. (2) Identifying the SaeRS controlled proteases which are required for quality control of protein secretion. (3) Investigating how SaeRS TCS regulates quality control of proteins secretion and combats secretion stress in S. aureus. The information derived from this study will provide new insights into the regulation pathway of protein secretion that are crucial to pathogenesis of S. aureus and be valuable for the development of effective strategies to prevent and control S. aureus infections.

Project ID:PC10907-0929
External Project ID:MOST109-2320-B182-038