Intracellular Zn(II) Intoxication Leads to Dysregulation of the PerR Regulon Resulting in Heme Toxicity in

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Zinc (Zn(II)) is often considered to be a “first among equals” in metal ion homeostasis. Zn(II) is critically important to the proper function of many cellular processes, yet is toxic at high levels. The molecular basis for Zn(II) intoxication is poorly understood. Using a forward genetic approach in B. subtilis, we demonstrate that elevated levels of external Zn(II) inhibit the electron transport chain, whereas intracellular Zn(II) intoxication is due to dysregulation of heme biosynthesis. Since the host immune system utilizes both Zn(II) sequestration and toxicity as a means of responding to pathogens, these findings contribute to our understanding of host-microbe interactions.

Vyšlo v časopise: Intracellular Zn(II) Intoxication Leads to Dysregulation of the PerR Regulon Resulting in Heme Toxicity in. PLoS Genet 12(12): e32767. doi:10.1371/journal.pgen.1006515
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1006515

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1. Irving H, Williams R. 637. The stability of transition-metal complexes. J Chem Soc. (Resumed). 1953: 3192–3210.

2. Outten CE, O'Halloran TV. Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science. 2001;292: 2488–2492. doi: 10.1126/science.1060331 11397910

3. Ma Z, Chandrangsu P, Helmann TC, Romsang A, Gaballa A, Helmann JD. Bacillithiol is a major buffer of the labile zinc pool in Bacillus subtilis. Mol Microbiol. 2014;94: 756–770. doi: 10.1111/mmi.12794 25213752

4. Gaballa A, Helmann JD. Identification of a zinc-specific metalloregulatory protein, Zur, controlling zinc transport operons in Bacillus subtilis. J Bacteriol. 1998;180: 5815–5821. 9811636

5. Moore CM, Gaballa A, Hui M, et al. Genetic and physiological responses of Bacillus subtilis to metal ion stress. Mol Microbiol. 2005;57: 27–40. doi: 10.1111/j.1365-2958.2005.04642.x 15948947

6. Harvie DR, Andreini C, Cavallaro G, Meng W, Connolly BA, Yoshida K-I, et al. Predicting metals sensed by ArsR-SmtB repressors: allosteric interference by a non-effector metal. Mol Microbiol. 2006;59: 1341–1356. doi: 10.1111/j.1365-2958.2006.05029.x 16430705

7. Ma Z, Gabriel SE, Helmann JD. Sequential binding and sensing of Zn(II) by Bacillus subtilis Zur. Nucleic Acids Res. 2011;39: 9130–9138. doi: 10.1093/nar/gkr625 21821657

8. Pennella MA, Shokes JE, Cosper NJ, Scott RA, Giedroc DP. Structural elements of metal selectivity in metal sensor proteins. Proc Natl Acad Sci USA. 2003;100: 3713–3718. doi: 10.1073/pnas.0636943100 12651949

9. Minasov G, Padavattan S, Shuvalova L, et al. Crystal structures of YkuI and its complex with second messenger cyclic Di-GMP suggest catalytic mechanism of phosphodiester bond cleavage by EAL domains. J Biol Chem. 2009;284: 13174–13184. doi: 10.1074/jbc.M808221200 19244251

10. Fagerlund A, Smith V, Røhr ÅK, Lindbäck T, Parmer MP, Andersson KK, et al. Cyclic diguanylate regulation of Bacillus cereus group biofilm formation. Mol Microbiol. 2016;101: 471–494. doi: 10.1111/mmi.13405 27116468

11. Márquez-Magaña LM, Chamberlin MJ. Characterization of the sigD transcription unit of Bacillus subtilis. J Bacteriol. 1994;176: 2427–2434. 8157612

12. Cairns LS, Marlow VL, Bissett E, Ostrowski A, Stanley-Wall NR. A mechanical signal transmitted by the flagellum controls signalling in Bacillus subtilis. Mol Microbiol. 2013;90: 6–21. doi: 10.1111/mmi.12342 23888912

13. Chan JM, Guttenplan SB, Kearns DB. Defects in the flagellar motor increase synthesis of poly-γ-glutamate in Bacillus subtilis. J Bacteriol. 2014;196: 740–753. doi: 10.1128/JB.01217-13 24296669

14. Brekasis D, Paget MSB. A novel sensor of NADH/NAD+ redox poise in Streptomyces coelicolor A3(2). EMBO J. 2003;22: 4856–4865. doi: 10.1093/emboj/cdg453 12970197

15. Larsson JT, Rogstam A, Wachenfeldt von C. Coordinated patterns of cytochrome bd and lactate dehydrogenase expression in Bacillus subtilis. Microbiology (Reading, Engl). 2005;151: 3323–3335.

16. Gyan S, Shiohira Y, Sato I, Takeuchi M, Sato T. Regulatory loop between redox sensing of the NADH/NAD(+) ratio by Rex (YdiH) and oxidation of NADH by NADH dehydrogenase Ndh in Bacillus subtilis. J Bacteriol. 2006;188: 7062–7071. doi: 10.1128/JB.00601-06 17015645

17. Wachenfeldt von C, Hederstedt L. Molecular biology of Bacillus subtilis cytochromes. FEMS Microbiology Letters. 1992;100: 91–100. 1335950

18. Winstedt L, Wachenfeldt von C. Terminal oxidases of Bacillus subtilis strain 168: one quinol oxidase, cytochrome aa(3) or cytochrome bd, is required for aerobic growth. J Bacteriol. 2000;182: 6557–6564. 11073895

19. Beard SJ, Hughes MN, Poole RK. Inhibition of the cytochrome bd-terminated NADH oxidase system in Escherichia coli K-12 by divalent metal cations. FEMS Microbiology Letters. 1995;131: 205–210. 7557331

20. Hoch JA, Nester EW. Gene-enzyme relationships of aromatic acid biosynthesis in Bacillus subtilis. J Bacteriol. 1973;116: 59–66. 4200844

21. Kobayashi K, Ehrlich SD, Albertini A, Amati G, Andersen KK, Arnaud M, et al. Essential Bacillus subtilis genes. Proc Natl Acad Sci USA. 2003;100: 4678–4683. doi: 10.1073/pnas.0730515100 12682299

22. Wakeman CA, Hammer ND, Stauff DL, et al. Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus. Mol Microbiol. 2012;86: 1376–1392. doi: 10.1111/mmi.12063 23043465

23. Gaballa A, Helmann JD. Bacillus subtilis Fur represses one of two paralogous haem-degrading monooxygenases. Microbiology (Reading, Engl). 2011;157: 3221–3231.

24. Anzaldi LL, Skaar EP. Overcoming the heme paradox: heme toxicity and tolerance in bacterial pathogens. Infect Immun. 2010;78: 4977–4989. doi: 10.1128/IAI.00613-10 20679437

25. Bsat N, Chen L, Helmann JD. Mutation of the Bacillus subtilis alkyl hydroperoxide reductase (ahpCF) operon reveals compensatory interactions among hydrogen peroxide stress genes. J Bacteriol. 1996;178: 6579–6586. 8932315

26. Chen L, Keramati L, Helmann JD. Coordinate regulation of Bacillus subtilis peroxide stress genes by hydrogen peroxide and metal ions. Proc Natl Acad Sci USA. 1995;92: 8190–8194. 7667267

27. Faulkner MJ, Ma Z, Fuangthong M, et al. Derepression of the Bacillus subtilis PerR Peroxide Stress Response Leads to Iron Deficiency. J Bacteriol. 2012;194: 1226–1235. doi: 10.1128/JB.06566-11 22194458

28. Herbig AF, Helmann JD. Roles of metal ions and hydrogen peroxide in modulating the interaction of the Bacillus subtilis PerR peroxide regulon repressor with operator DNA. Mol Microbiol. 2001;41: 849–859. 11532148

29. Fuangthong M, Herbig AF, Bsat N, et al. Regulation of the Bacillus subtilis fur and perR genes by PerR: not all members of the PerR regulon are peroxide inducible. J Bacteriol. 2002;184: 3276–3286. doi: 10.1128/JB.184.12.3276-3286.2002 12029044

30. Lee J-W, Helmann JD. The PerR transcription factor senses H2O2 by metal-catalysed histidine oxidation. Nature. 2006;440: 363–367. doi: 10.1038/nature04537 16541078

31. Helmann JD. Specificity of metal sensing: iron and manganese homeostasis in Bacillus subtilis. J Biol Chem. 2014;289: 28112–28120. doi: 10.1074/jbc.R114.587071 25160631

32. Lee J-W, Helmann JD. Functional specialization within the Fur family of metalloregulators. Biometals. 2007;20: 485–499. doi: 10.1007/s10534-006-9070-7 17216355

33. Ma Z, Lee J-W, Helmann JD. Identification of altered function alleles that affect Bacillus subtilis PerR metal ion selectivity. Nucleic Acids Res. 2011;39: 5036–5044. doi: 10.1093/nar/gkr095 21398634

34. Lee J-W, Helmann JD. Biochemical characterization of the structural Zn2+ site in the Bacillus subtilis peroxide sensor PerR. J Biol Chem. 2006;281: 23567–23578. doi: 10.1074/jbc.M603968200 16766519

35. Chen L, Helmann JD. Bacillus subtilis MrgA is a Dps(PexB) homologue: evidence for metalloregulation of an oxidative-stress gene. Mol Microbiol. 1995;18: 295–300. 8709848

36. Fuangthong M, Helmann JD. Recognition of DNA by three ferric uptake regulator (Fur) homologs in Bacillus subtilis. J Bacteriol. 2003;185: 6348–6357. doi: 10.1128/JB.185.21.6348-6357.2003 14563870

37. Djoko KY, Ong C-LY, Walker MJ, et al. Copper and zinc toxicity and its role in innate immune defense against bacterial pathogens. Journal of Biological Chemistry. 2015.

38. McDevitt CA, Ogunniyi AD, Valkov E, et al. A molecular mechanism for bacterial susceptibility to zinc. PLoS Pathog. 2011;7: e1002357. doi: 10.1371/journal.ppat.1002357 22072971

39. Dintilhac A, Alloing G, Granadel C, Claverys JP. Competence and virulence of Streptococcus pneumoniae: Adc and PsaA mutants exhibit a requirement for Zn and Mn resulting from inactivation of putative ABC metal permeases. Mol Microbiol. 1997;25: 727–739. 9379902

40. Skulachev VP, Chistyakov VV, Jasaitis AA, Smirnova EG. Inhibition of the respiratory chain by zinc ions. Biochem Biophys Res Commun. 1967;26: 1–6. 4291553

41. Lee D-W, Khoury El Y, Francia F, et al. Zinc inhibition of bacterial cytochrome bc(1) reveals the role of cytochrome b E295 in proton release at the Q(o) site. Biochemistry. 2011;50: 4263–4272. doi: 10.1021/bi200230e 21500804

42. Vygodina TV, Zakirzianova W, Konstantinov AA. Inhibition of membrane-bound cytochrome c oxidase by zinc ions: high-affinity Zn2+-binding site at the P-side of the membrane. FEBS Lett. 2008;582: 4158–4162. doi: 10.1016/j.febslet.2008.11.018 19041645

43. Kuznetsova SS, Azarkina NV, Vygodina TV, Siletsky SA, Konstantinov AA. Zinc ions as cytochrome C oxidase inhibitors: two sites of action. Biochemistry Mosc. 2005;70: 128–136. 15807649

44. Korshunov S, Imlay KRC, Imlay JA. The cytochrome bd oxidase of Escherichia coli prevents respiratory inhibition by endogenous and exogenous hydrogen sulfide. Mol Microbiol. 2016.

45. Hammer ND, Reniere ML, Cassat JE, Zhang Y, Hirsch AO, Indriati Hood M, et al. Two heme-dependent terminal oxidases power Staphylococcus aureus organ-specific colonization of the vertebrate host. MBio. 2013;4.

46. Shi L, Sohaskey CD, Kana BD, Dawes S, North RJ, Mizrahi V, et al. Changes in energy metabolism of Mycobacterium tuberculosis in mouse lung and under in vitro conditions affecting aerobic respiration. Proc Natl Acad Sci USA. 2005;102: 15629–15634. doi: 10.1073/pnas.0507850102 16227431

47. Jones SA, Chowdhury FZ, Fabich AJ, Anderson A, Schreiner DM, House AL, et al. Respiration of Escherichia coli in the mouse intestine. Infect Immun. 2007;75: 4891–4899. doi: 10.1128/IAI.00484-07 17698572

48. Surmann K, Michalik S, Hildebrandt P, Gierok P, Depke M, Brinkmann L, et al. Comparative proteome analysis reveals conserved and specific adaptation patterns of Staphylococcus aureus after internalization by different types of human non-professional phagocytic host cells. Front Microbiol. 2014;5: 392. doi: 10.3389/fmicb.2014.00392 25136337

49. Vlamakis H, Chai Y, Beauregard P, Losick R, Kolter R. Sticking together: building a biofilm the Bacillus subtilis way. Nat Rev Microbiol. 2013;11: 157–168. doi: 10.1038/nrmicro2960 23353768

50. Navarrete F, La Fuente De L. Response of Xylella fastidiosa to zinc: decreased culturability, increased exopolysaccharide production, and formation of resilient biofilms under flow conditions. Appl Environ Microbiol. 2014;80: 1097–1107. doi: 10.1128/AEM.02998-13 24271184

51. Wang D, Fierke CA. The BaeSR regulon is involved in defense against zinc toxicity in E. coli. Metallomics. 2013;5: 372–383. doi: 10.1039/c3mt20217h 23446818

52. Ong C-LY, Walker MJ, McEwan AG. Zinc disrupts central carbon metabolism and capsule biosynthesis in Streptococcus pyogenes. Sci Rep. 2015;5: 10799. doi: 10.1038/srep10799 26028191

53. Anjem A, Imlay JA. Mononuclear iron enzymes are primary targets of hydrogen peroxide stress. Journal of Biological Chemistry. 2012;287: 15544–15556. doi: 10.1074/jbc.M111.330365 22411989

54. Xu FF, Imlay JA. Silver(I), mercury(II), cadmium(II), and zinc(II) target exposed enzymic iron-sulfur clusters when they toxify Escherichia coli. Appl Environ Microbiol. 2012;78: 3614–3621. doi: 10.1128/AEM.07368-11 22344668

55. Brenot A, Weston BF, Caparon MG. A PerR-regulated metal transporter (PmtA) is an interface between oxidative stress and metal homeostasis in Streptococcus pyogenes. Mol Microbiol. 2007;63: 1185–1196. doi: 10.1111/j.1365-2958.2006.05577.x 17238923

56. Guan G, Pinochet-Barros A, Gaballa A, Patel SJ, Argüello JM, Helmann JD. PfeT, a P1B4 -type ATPase, effluxes ferrous iron and protects Bacillus subtilis against iron intoxication. Mol Microbiol. 2015;98: 787–803. doi: 10.1111/mmi.13158 26261021

57. Pi H, Patel SJ, Argüello JM, Helmann JD. The Listeria monocytogenes Fur-regulated virulence protein FrvA is an Fe(II) efflux P1B4 -type ATPase. Mol Microbiol. 2016;100: 1066–1079. doi: 10.1111/mmi.13368 26946370

58. Raimunda D, Long JE, Padilla-Benavides T, Sassetti CM, Argüello JM. Differential roles for the Co(2+) /Ni(2+) transporting ATPases, CtpD and CtpJ, in Mycobacterium tuberculosis virulence. Mol Microbiol. 2014;91: 185–197. doi: 10.1111/mmi.12454 24255990

59. Baichoo N, Wang T, Ye R, Helmann JD. Global analysis of the Bacillus subtilis Fur regulon and the iron starvation stimulon. Mol Microbiol. 2002;45: 1613–1629. 12354229

60. Tao X, Zeng HY, Murphy JR. Transition metal ion activation of DNA binding by the diphtheria tox repressor requires the formation of stable homodimers. Proc Natl Acad Sci USA. 1995;92: 6803–6807. 7624323

61. Gilston BA, Wang S, Marcus MD, Canalizo-Hernández MA, Swindell EP, Xue Y, et al. Structural and mechanistic basis of zinc regulation across the E. coli Zur regulon. PLoS Biol. 2014;12: e1001987. doi: 10.1371/journal.pbio.1001987 25369000

62. Ma Z, Faulkner MJ, Helmann JD. Origins of specificity and cross-talk in metal ion sensing by Bacillus subtilis Fur. Mol Microbiol. 2012;86: 1144–1155. doi: 10.1111/mmi.12049 23057863

63. Begg SL, Eijkelkamp BA, Luo Z, et al. Dysregulation of transition metal ion homeostasis is the molecular basis for cadmium toxicity in Streptococcus pneumoniae. Nat Commun. 2015;6: 6418. doi: 10.1038/ncomms7418 25731976

64. Turner AG, Ong C-LY, Gillen CM, et al. Manganese homeostasis in group A Streptococcus is critical for resistance to oxidative stress and virulence. MBio. 2015;6.

65. Botella H, Peyron P, Levillain F, et al. Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages. Cell Host Microbe. 2011;10: 248–259. doi: 10.1016/j.chom.2011.08.006 21925112

66. Ong C-LY, Gillen CM, Barnett TC, et al. An antimicrobial role for zinc in innate immune defense against group A streptococcus. J Infect Dis. 2014;209: 1500–1508. doi: 10.1093/infdis/jiu053 24449444

67. Kapetanovic R, Bokil NJ, Achard MES, Ong C-LY, Peters KM, Stocks CJ, et al. Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages. FASEB J. 2016.

68. Abrantes MC, Kok J, Silva Lopes M de F. Enterococcus faecalis zinc-responsive proteins mediate bacterial defence against zinc overload, lysozyme and oxidative stress. Microbiology (Reading, Engl). 2014;160: 2755–2762.

69. Mascher T, Margulis NG, Wang T, Ye RW, Helmann JD. Cell wall stress responses in Bacillus subtilis: the regulatory network of the bacitracin stimulon. Mol Microbiol. 2003;50: 1591–1604. 14651641

70. Faulkner MJ, Ma Z, Fuangthong M, Helmann JD. Derepression of the Bacillus subtilis PerR peroxide stress response leads to iron deficiency. J Bacteriol. 2012;194: 1226–1235. doi: 10.1128/JB.06566-11 22194458