The membrane protein PrsS mimics σS in protecting Staphylococcus aureus against cell wall-targeting antibiotics and DNA-damaging agents.
Staphylococcus aureus possesses a lone extracytoplasmic function (ECF) sigma factor, σ(S). In Bacillus subtilis, the ECF sigma factor, σ(W), is activated through a proteolytic cascade that begins with cleavage of the RsiW anti-sigma factor by a site-1 protease (S1P), PrsW. We have identified a PrsW homologue in S. aureus (termed PrsS) and explored its role in σ(S) regulation. Herein, we demonstrate that although a cognate σ(S) anti-sigma factor currently remains elusive, prsS phenocopies sigS in a wealth of regards. Specifically, prsS expression mimics the upregulation observed for sigS in response to DNA-damaging agents, cell wall-targeting antibiotics and during ex vivo growth in human serum and murine macrophages. prsS mutants also display the same sensitivities of sigS mutants to the DNA-damaging agents methyl methane sulfonate (MMS) and hydrogen peroxide, and the cell wall-targeting antibiotics ampicillin, bacitracin and penicillin-G. These phenotypes appear to be explained by alterations in abundance of proteins involved in drug resistance (Pbp2a, FemB, HmrA) and the response to DNA damage (BmrA, Hpt, Tag). Our findings seem to be mediated by putative proteolytic activity of PrsS, as site-directed mutagenesis of predicted catalytic residues fails to rescue the sensitivity of the mutant to H2O2 and MMS. Finally, a role for PrsS in S. aureus virulence was identified using human and murine models of infection. Collectively, our data indicate that PrsS and σ(S) function in a similar manner, and perhaps mediate virulence and resistance to DNA damage and cell wall-targeting antibiotics, via a common pathway.
Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, FL, USA.
Christina N
CN
Krute
Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, FL, USA.
Harris
H
Bell-Temin
Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, FL, USA.
Halie K
HK
Miller
Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, FL, USA.
Frances E
FE
Rivera
Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, FL, USA.
Andy
A
Weiss
Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, FL, USA.
Stanley M
SM
Stevens
Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, FL, USA.
Lindsey N
LN
Shaw
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D024881:Drug Resistance, Bacterial; D015870:Gene Expression; D015964:Gene Expression Regulation, Bacterial; D017930:Genes, Reporter; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D040901:Proteomics; D012808:Sigma Factor / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D013552:Swine; D024363:Transcription Initiation Site
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008565:Membrane Proteins; D012808:Sigma Factor