The Extracytoplasmic Linker Peptide of the Sensor Protein SaeS Tunes the Kinase Activity Required for Staphylococcal Virulence in Response to Host Signals

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A bacterial pathogen Staphylococcus aureus uses the SaeRS two-component system to control the production of multiple toxins, resulting in a wide range of diseases in human. The sensor kinase SaeS is a member of the intramembrane-sensing histidine kinases (IM-HKs) that lacks a sensory domain and harbors a simple N-terminal domain with two transmembrane helices and a short linker peptide. It’s been considered that the linker peptide of IM-HKs transmits the external signals into the cytoplasmic catalytic domain to control the HK’s kinase activity. However, it is unclear how the external signal input propagates through the linker to modulate the kinase activity of HKs. Here we show that the linker peptide of SaeS is critical in maintaining the basal kinase activity and functions as a part of a “tripwire” to jumpstart the activation of the SaeRS system upon exposure to the specific host signals. We establish that a single amino acid substitution of the linker peptide alters SaeS’s kinase activity, resulting in different expression levels of the SaeR-activated genes and alteration of the bacterial virulence in mice. Our study provides new molecular insights into how the pathogenic bacterium utilizes the simple protein domain to control its disease-causing potentials in response to host immune signals.

Vyšlo v časopise: The Extracytoplasmic Linker Peptide of the Sensor Protein SaeS Tunes the Kinase Activity Required for Staphylococcal Virulence in Response to Host Signals. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004799
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004799

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Zdroje

1. Beier D, Gross R (2006) Regulation of bacterial virulence by two-component systems. Curr Opin Microbiol 9: 143–152. 16481212

2. Stock AM, Robinson VL, Goudreau PN (2000) Two-component signal transduction. Annu Rev Biochem 69: 183–215. 10966457

3. Bourret RB (2010) Receiver domain structure and function in response regulator proteins. Curr Opin Microbiol 13: 142–149. doi: 10.1016/j.mib.2010.01.015 20211578

4. Hoch JA (2000) Two-component and phosphorelay signal transduction. Curr Opin Microbiol 3: 165–170. 10745001

5. West AH, Stock AM (2001) Histidine kinases and response regulator proteins in two-component signaling systems. Trends Biochem Sci 26: 369–376. 11406410

6. Mascher T (2006) Intramembrane-sensing histidine kinases: a new family of cell envelope stress sensors in Firmicutes bacteria. FEMS Microbiol Lett 264: 133–144. 17064367

7. Bernard R, Guiseppi A, Chippaux M, Foglino M, Denizot F (2007) Resistance to bacitracin in Bacillus subtilis: unexpected requirement of the BceAB ABC transporter in the control of expression of its own structural genes. J Bacteriol 189: 8636–8642. 17905982

8. Jordan S, Junker A, Helmann JD, Mascher T (2006) Regulation of LiaRS-Dependent Gene Expression in Bacillus subtilis: Identification of Inhibitor Proteins, Regulator Binding Sites, and Target Genes of a Conserved Cell Envelope Stress-Sensing Two-Component System. J Bacteriol 188: 5153–5166. 16816187

9. Mascher T (2014) Bacterial (intramembrane-sensing) histidine kinases: signal transfer rather than stimulus perception. Trends Microbiol. 22: 559–565. doi: 10.1016/j.tim.2014.05.006 24947190

10. Giraudo AT, Cheung AL, Nagel R (1997) The sae locus of Staphylococcus aureus controls exoprotein synthesis at the transcriptional level. Arch Microbiol 168: 53–58. 9211714

11. Goerke C, Fluckiger U, Steinhuber A, Bisanzio V, Ulrich M, et al. (2005) Role of Staphylococcus aureus global regulators sae and sigmaB in virulence gene expression during device-related infection. Infect Immun 73: 3415–3421. 15908369

12. Liang X, Yu C, Sun J, Liu H, Landwehr C, et al. (2006) Inactivation of a two-component signal transduction system, SaeRS, eliminates adherence and attenuates virulence of Staphylococcus aureus. Infect Immun 74: 4655–4665. 16861653

13. Rogasch K, Ruhmling V, Pane-Farre J, Hoper D, Weinberg C, et al. (2006) Influence of the two-component system SaeRS on global gene expression in two different Staphylococcus aureus strains. J Bacteriol 188: 7742–7758. 17079681

14. Voyich JM, Vuong C, DeWald M, Nygaard TK, Kocianova S, et al. (2009) The SaeR/S gene regulatory system is essential for innate immune evasion by Staphylococcus aureus. J Infect Dis 199: 1698–1706. doi: 10.1086/598967 19374556

15. Xiong YQ, Willard J, Yeaman MR, Cheung AL, Bayer AS (2006) Regulation of Staphylococcus aureus alpha-toxin gene (hla) expression by agr, sarA, and sae in vitro and in experimental infective endocarditis. J Infect Dis 194: 1267–1275. 17041853

16. Jeong DW, Cho H, Jones MB, Shatzkes K, Sun F, et al. (2012) The auxiliary protein complex SaePQ activates the phosphatase activity of sensor kinase SaeS in the SaeRS two-component system of Staphylococcus aureus. Mol Microbiol. 86: 331–348. doi: 10.1111/j.1365-2958.2012.08198.x 22882143

17. Jeong DW, Cho H, Lee H, Li C, Garza J, et al. (2011) Identification of the P3 promoter and distinct roles of the two promoters of the SaeRS two-component system in Staphylococcus aureus. J Bacteriol 193: 4672–4684. doi: 10.1128/JB.00353-11 21764914

18. Mainiero M, Goerke C, Geiger T, Gonser C, Herbert S, et al. (2010) Differential target gene activation by the Staphylococcus aureus two-component system saeRS. J Bacteriol 192: 613–623. doi: 10.1128/JB.01242-09 19933357

19. Cho H, Jeong DW, Li C, Bae T (2012) Organizational requirements of the SaeR binding sites for functional P1 promoter of the sae operon in Staphylococcus aureus. J Bacteriol. 194: 2865–2876. doi: 10.1128/JB.06771-11 22447906

20. Adhikari RP, Novick RP (2008) Regulatory organization of the staphylococcal sae locus. Microbiology 154: 949–959. doi: 10.1099/mic.0.2007/012245-0 18310041

21. Omae Y, Hanada Y, Sekimizu K, Kaito C (2013) Silkworm apolipophorin protein inhibits hemolysin gene expression of Staphylococcus aureus via binding to cell surface lipoteichoic acids. J Biol Chem. 288: 25542–25550. doi: 10.1074/jbc.M113.495051 23873929

22. Manoil C, Beckwith J (1986) A genetic approach to analyzing membrane protein topology. Science 233: 1403–1408. 3529391

23. Flack CE, Zurek OW, Meishery DD, Pallister KB, Malone CL, et al. (2014) Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli. Proc Natl Acad Sci U S A. 111: E2037–2045. doi: 10.1073/pnas.1322125111 24782537

24. Eisenhauer PB, Lehrer RI (1992) Mouse neutrophils lack defensins. Infect Immun 60: 3446–3447. 1639513

25. Zurek OW, Nygaard TK, Watkins RL, Pallister KB, Torres VJ, et al. (2013) The Role of Innate Immunity in Promoting SaeR/S-Mediated Virulence in Staphylococcus aureus. J Innate Immun. 6: 21–30. doi: 10.1159/000351200 23816635

26. Geiger T, Goerke C, Mainiero M, Kraus D, Wolz C (2008) The virulence regulator Sae of Staphylococcus aureus: promoter activities and response to phagocytosis-related signals. J Bacteriol 190: 3419–3428. doi: 10.1128/JB.01927-07 18344360

27. Boyle-Vavra S, Yin S, Jo DS, Montgomery CP, Daum RS (2013) VraT/YvqF is required for methicillin resistance and activation of the VraSR regulon in Staphylococcus aureus. Antimicrob Agents Chemother 57: 83–95. doi: 10.1128/AAC.01651-12 23070169

28. Coumes-Florens S, Brochier-Armanet C, Guiseppi A, Denizot F, Foglino M (2011) A new highly conserved antibiotic sensing/resistance pathway in firmicutes involves an ABC transporter interplaying with a signal transduction system. PLoS One 6: e15951. doi: 10.1371/journal.pone.0015951 21283517

29. Falord M, Karimova G, Hiron A, Msadek T (2012) GraXSR proteins interact with the VraFG ABC transporter to form a five-component system required for cationic antimicrobial peptide sensing and resistance in Staphylococcus aureus. Antimicrob Agents Chemother 56: 1047–1058. doi: 10.1128/AAC.05054-11 22123691

30. Hiron A, Falord M, Valle J, Debarbouille M, Msadek T (2011) Bacitracin and nisin resistance in Staphylococcus aureus: a novel pathway involving the BraS/BraR two-component system (SA2417/SA2418) and both the BraD/BraE and VraD/VraE ABC transporters. Mol Microbiol 81: 602–622. doi: 10.1111/j.1365-2958.2011.07735.x 21696458

31. Kuroda H, Kuroda M, Cui L, Hiramatsu K (2007) Subinhibitory concentrations of beta-lactam induce haemolytic activity in Staphylococcus aureus through the SaeRS two-component system. FEMS Microbiol Lett 268: 98–105. 17263851

32. Hanahan D (1983) Studies on transformation of Escherichia coli with plasmids. J Mol Biol 166: 557–580. 6345791

33. Donnelly MI, Zhou M, Millard CS, Clancy S, Stols L, et al. (2006) An expression vector tailored for large-scale, high-throughput purification of recombinant proteins. Protein Expr Purif 47: 446–454. 16497515

34. Bae T, Schneewind O (2006) Allelic replacement in Staphylococcus aureus with inducible counter-selection. Plasmid 55: 58–63. 16051359

35. Payne MS, Jackson EN (1991) Use of alkaline phosphatase fusions to study protein secretion in Bacillus subtilis. J Bacteriol 173: 2278–2282. 1901054

36. Li MZ, Elledge SJ (2012) SLIC: a method for sequence- and ligation-independent cloning. Methods Mol Biol 852: 51–59. doi: 10.1007/978-1-61779-564-0_5 22328425

37. Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR (1989) Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77: 51–59. 2744487

38. Sastalla I, Chim K, Cheung GY, Pomerantsev AP, Leppla SH (2009) Codon-optimized fluorescent proteins designed for expression in low-GC gram-positive bacteria. Appl Environ Microbiol 75: 2099–2110. doi: 10.1128/AEM.02066-08 19181829

39. Boyum A (1968) Separation of leukocytes from blood and bone marrow. Introduction. Scand J Clin Lab Invest Suppl 97: 7. 5707208

40. Sayers EW, Barrett T, Benson DA, Bolton E, Bryant SH, et al. (2012) Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 40: D13–25. doi: 10.1093/nar/gkr1184 22140104

41. Crooks GE, Hon G, Chandonia JM, Brenner SE (2004) WebLogo: a sequence logo generator. Genome Res 14: 1188–1190. 15173120