Mitochondrial Activity and Cyr1 Are Key Regulators of Ras1 Activation of . Virulence Pathways

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Candida albicans is a successful fungal commensal and pathogen of humans. It is a polymorphic organism and the ability to switch from yeast to hyphal growth is associated with the commensal-to-pathogen switch. Previous research identified the Ras1-cAMP-protein kinase A pathway as a key regulator of hyphal growth. Here, we report that mitochondrial activity plays a key role in Ras1 activation, as respiratory inhibition decreased Ras1 activity and Ras1-dependent filamentation. We found that intracellular ATP modulates Ras1 activity through a pathway involving the GTPase activating protein Ira2 and the adenylate cyclase Cyr1. Based on our data the canonical Ras1 signaling model in C. albicans needs to be restructured in such a way that Cyr1 is no longer placed downstream of Ras1 but rather in a major signaling node with Ras1 and Ira2. Our studies suggest that the energy status of the cell is the most important signal involved in the decision of C. albicans to undergo the yeast-to-hyphae switch or express genes associated with the hyphal morphology as low intracellular ATP or associated cues override several hypha-inducing signals. Future studies will show if this knowledge can be used to develop therapies that would favor benign host-Candida interactions by promoting low Ras1 activity.

Vyšlo v časopise: Mitochondrial Activity and Cyr1 Are Key Regulators of Ras1 Activation of . Virulence Pathways. PLoS Pathog 11(8): e32767. doi:10.1371/journal.ppat.1005133
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005133

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1. Pfaller MA, Diekema DJ (2010) Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36: 1–53. doi: 10.3109/10408410903241444 20088682

2. Casalinuovo IA, Di Francesco P, Garaci E (2004) Fluconazole resistance in Candida albicans: a review of mechanisms. Eur Rev Med Pharmacol Sci 8: 69–77. 15267120

3. Peters BM, Palmer GE, Nash AK, Lilly EA, Fidel PL Jr., et al. (2014) Fungal morphogenetic pathways are required for the hallmark inflammatory response during Candida albicans vaginitis. Infect Immun 82: 532–543. doi: 10.1128/IAI.01417-13 24478069

4. Lo HJ, Kohler JR, DiDomenico B, Loebenberg D, Cacciapuoti A, et al. (1997) Nonfilamentous C. albicans mutants are avirulent. Cell 90: 939–949. 9298905

5. Mitchell AP (1998) Dimorphism and virulence in Candida albicans. Curr Opin Microbiol 1: 687–692. 10066539

6. Hogan DA, Sundstrom P (2009) The Ras/cAMP/PKA signaling pathway and virulence in Candida albicans. Future Microbiol 4: 1263–1270. doi: 10.2217/fmb.09.106 19995187

7. Kashkin PN, Krassilnicov NA, Nekachalov VY (1961) Candida complications after antibiotic therapy. Mycopathologia 14: 173–188. 13751663

8. Samonis G, Anastassiadou H, Dassiou M, Tselentis Y, Bodey GP (1994) Effects of broad-spectrum antibiotics on colonization of gastrointestinal tracts of mice by Candida albicans. Antimicrob Agents Chemother 38: 602–603. 8203861

9. Samonis G, Gikas A, Toloudis P, Maraki S, Vrentzos G, et al. (1994) Prospective study of the impact of broad-spectrum antibiotics on the yeast flora of the human gut. Eur J Clin Microbiol Infect Dis 13: 665–667. 7813500

10. Krcmery V Jr., Matejicka F, Pichnova E, Jurga L, Sulcova M, et al. (1999) Documented fungal infections after prophylaxis or therapy with wide spectrum antibiotics: relationship between certain fungal pathogens and particular antimicrobials? J Chemother 11: 385–390. 10632385

11. Xu J, Schwartz K, Bartoces M, Monsur J, Severson RK, et al. (2008) Effect of antibiotics on vulvovaginal candidiasis: a MetroNet study. J Am Board Fam Med 21: 261–268. doi: 10.3122/jabfm.2008.04.070169 18612052

12. Lynch AS, Robertson GT (2008) Bacterial and fungal biofilm infections. Annu Rev Med 59: 415–428. 17937586

13. Peleg AY, Hogan DA, Mylonakis E (2010) Medically important bacterial-fungal interactions. Nat Rev Microbiol 8: 340–349. doi: 10.1038/nrmicro2313 20348933

14. Morales DK, Hogan DA (2010) Candida albicans interactions with bacteria in the context of human health and disease. PLoS Pathog 6: e1000886. doi: 10.1371/journal.ppat.1000886 20442787

15. Davis-Hanna A, Piispanen AE, Stateva LI, Hogan DA (2008) Farnesol and dodecanol effects on the Candida albicans Ras1-cAMP signalling pathway and the regulation of morphogenesis. Mol Microbiol 67: 47–62. 18078440

16. Hall RA, Turner KJ, Chaloupka J, Cottier F, De Sordi L, et al. (2011) The quorum-sensing molecules farnesol/homoserine lactone and dodecanol operate via distinct modes of action in Candida albicans. Eukaryot Cell 10: 1034–1042. doi: 10.1128/EC.05060-11 21666074

17. Rocha CR, Schroppel K, Harcus D, Marcil A, Dignard D, et al. (2001) Signaling through adenylyl cyclase is essential for hyphal growth and virulence in the pathogenic fungus Candida albicans. Mol Biol Cell 12: 3631–3643. 11694594

18. Leberer E, Harcus D, Dignard D, Johnson L, Ushinsky S, et al. (2001) Ras links cellular morphogenesis to virulence by regulation of the MAP kinase and cAMP signalling pathways in the pathogenic fungus Candida albicans. Mol Microbiol 42: 673–687. 11722734

19. Park H, Myers CL, Sheppard DC, Phan QT, Sanchez AA, et al. (2005) Role of the fungal Ras-protein kinase A pathway in governing epithelial cell interactions during oropharyngeal candidiasis. Cell Microbiol 7: 499–510. 15760450

20. Boguski MS, McCormick F (1993) Proteins regulating Ras and its relatives. Nature 366: 643–654. 8259209

21. Feng Q, Summers E, Guo B, Fink G (1999) Ras signaling is required for serum-induced hyphal differentiation in Candida albicans. J Bacteriol 181: 6339–6346. 10515923

22. Fang HM, Wang Y (2006) RA domain-mediated interaction of Cdc35 with Ras1 is essential for increasing cellular cAMP level for Candida albicans hyphal development. Mol Microbiol 61: 484–496. 16856944

23. Cassola A, Parrot M, Silberstein S, Magee BB, Passeron S, et al. (2004) Candida albicans lacking the gene encoding the regulatory subunit of protein kinase A displays a defect in hyphal formation and an altered localization of the catalytic subunit. Eukaryot Cell 3: 190–199. 14871949

24. Zelada A, Castilla R, Passeron S, Giasson L, Cantore ML (2002) Interactions between regulatory and catalytic subunits of the Candida albicans cAMP-dependent protein kinase are modulated by autophosphorylation of the regulatory subunit. Biochim Biophys Acta 1542: 73–81. 11853881

25. Mayer FL, Wilson D, Hube B (2013) Candida albicans pathogenicity mechanisms. Virulence 4: 119–128. doi: 10.4161/viru.22913 23302789

26. Yi S, Sahni N, Daniels KJ, Lu KL, Srikantha T, et al. (2011) Alternative mating type configurations (a/alpha versus a/a or alpha/alpha) of Candida albicans result in alternative biofilms regulated by different pathways. PLoS Biol 9: e1001117. doi: 10.1371/journal.pbio.1001117 21829325

27. Huang G, Yi S, Sahni N, Daniels KJ, Srikantha T, et al. (2010) N-acetylglucosamine induces white to opaque switching, a mating prerequisite in Candida albicans. PLoS Pathog 6: e1000806. doi: 10.1371/journal.ppat.1000806 20300604

28. Kerr JR, Taylor GW, Rutman A, Hoiby N, Cole PJ, et al. (1999) Pseudomonas aeruginosa pyocyanin and 1-hydroxyphenazine inhibit fungal growth. J Clin Pathol 52: 385–387. 10560362

29. Morales DK, Grahl N, Okegbe C, Dietrich LE, Jacobs NJ, et al. (2013) Control of Candida albicans metabolism and biofilm formation by Pseudomonas aeruginosa phenazines. MBio 4: e00526–00512. doi: 10.1128/mBio.00526-12 23362320

30. Laursen JB, Nielsen J (2004) Phenazine natural products: biosynthesis, synthetic analogues, and biological activity. Chem Rev 104: 1663–1686. 15008629

31. French SW, Palmer DS, Sim WA (1973) Phenazine methosulfate uptake by rat liver mitochondria. Can J Biochem 51: 235–240. 4700341

32. O'Malley YQ, Abdalla MY, McCormick ML, Reszka KJ, Denning GM, et al. (2003) Subcellular localization of Pseudomonas pyocyanin cytotoxicity in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 284: L420–430. 12414438

33. O'Malley YQ, Reszka KJ, Rasmussen GT, Abdalla MY, Denning GM, et al. (2003) The Pseudomonas secretory product pyocyanin inhibits catalase activity in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 285: L1077–1086. 12871859

34. Guedouari H, Gergondey R, Bourdais A, Vanparis O, Bulteau AL, et al. (2014) Changes in glutathione-dependent redox status and mitochondrial energetic strategies are part of the adaptive response during the filamentation process in Candida albicans. Biochim Biophys Acta 1842: 1855–1869. doi: 10.1016/j.bbadis.2014.07.006 25018088

35. Armstrong AV, Stewart-Tull DE (1971) The site of the activity of extracellular products of Pseudomonas aeruginosa in the electron-transport chain in mammalian cell respiration. J Med Microbiol 4: 263–270. 4328182

36. Armstrong AV, Stewart-Tull DE, Roberts JS (1971) Characterisation of the Pseudomonas aeruginosa factor that inhibits mouse-liver mitochondrial respiration. J Med Microbiol 4: 249–262. 4998856

37. Stewart-Tull DE, Armstrong AV (1972) The effect of 1-hydroxyphenazine and pyocyanin from Pseudomonas aeruginosa on mammalian cell respiration. J Med Microbiol 5: 67–73. 4623349

38. Hamanaka RB, Chandel NS (2010) Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci 35: 505–513. doi: 10.1016/j.tibs.2010.04.002 20430626

39. Tait SW, Green DR (2012) Mitochondria and cell signalling. J Cell Sci 125: 807–815. doi: 10.1242/jcs.099234 22448037

40. Kasozi DM, Gromer S, Adler H, Zocher K, Rahlfs S, et al. (2011) The bacterial redox signaller pyocyanin as an antiplasmodial agent: comparisons with its thioanalog methylene blue. Redox Rep 16: 154–165. doi: 10.1179/174329211X13049558293678 21888766

41. Schirmer RH, Adler H, Pickhardt M, Mandelkow E (2011) "Lest we forget you—methylene blue…". Neurobiol Aging 32: 2325 e2327–2316.

42. Saville SP, Lazzell AL, Monteagudo C, Lopez-Ribot JL (2003) Engineered control of cell morphology in vivo reveals distinct roles for yeast and filamentous forms of Candida albicans during infection. Eukaryot Cell 2: 1053–1060. 14555488

43. Lee KK, Boelsterli UA (2014) Bypassing the compromised mitochondrial electron transport with methylene blue alleviates efavirenz/isoniazid-induced oxidant stress and mitochondria-mediated cell death in mouse hepatocytes. Redox Biol 2C: 599–609. doi: 10.1016/j.redox.2014.03.003 25460728

44. Lindsay AK, Morales DK, Liu Z, Grahl N, Zhang A, et al. (2014) Analysis of Candida albicans mutants defective in the Cdk8 module of mediator reveal links between metabolism and biofilm formation. PLoS Genet 10: e1004567. doi: 10.1371/journal.pgen.1004567 25275466

45. McDonough JA, Bhattacherjee V, Sadlon T, Hostetter MK (2002) Involvement of Candida albicans NADH dehydrogenase complex I in filamentation. Fungal Genet Biol 36: 117–127. 12081465

46. Stoldt VR, Sonneborn A, Leuker CE, Ernst JF (1997) Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi. EMBO J 16: 1982–1991. 9155024

47. Bockmuhl DP, Ernst JF (2001) A potential phosphorylation site for an A-type kinase in the Efg1 regulator protein contributes to hyphal morphogenesis of Candida albicans. Genetics 157: 1523–1530. 11290709

48. Sonneborn A, Bockmuhl DP, Gerads M, Kurpanek K, Sanglard D, et al. (2000) Protein kinase A encoded by TPK2 regulates dimorphism of Candida albicans. Mol Microbiol 35: 386–396. 10652099

49. Braun BR, Johnson AD (1997) Control of filament formation in Candida albicans by the transcriptional repressor TUP1. Science 277: 105–109. 9204892

50. Johnston DA, Tapia AL, Eberle KE, Palmer GE (2013) Three prevacuolar compartment Rab GTPases impact Candida albicans hyphal growth. Eukaryot Cell 12: 1039–1050. doi: 10.1128/EC.00359-12 23709183

51. Piispanen AE, Bonnefoi O, Carden S, Deveau A, Bassilana M, et al. (2011) Roles of Ras1 membrane localization during Candida albicans hyphal growth and farnesol response. Eukaryot Cell 10: 1473–1484. doi: 10.1128/EC.05153-11 21908593

52. Piispanen AE, Grahl N, Hollomon JM, Hogan DA (2013) Regulated proteolysis of Candida albicans Ras1 is involved in morphogenesis and quorum sensing regulation. Mol Microbiol 89: 166–178. doi: 10.1111/mmi.12268 23692372

53. Visarius TM, Stucki JW, Lauterburg BH (1999) Inhibition and stimulation of long-chain fatty acid oxidation by chloroacetaldehyde and methylene blue in rats. J Pharmacol Exp Ther 289: 820–824. 10215658

54. Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25: 1895–1908. doi: 10.1101/gad.17420111 21937710

55. Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13: 251–262. doi: 10.1038/nrm3311 22436748

56. Celenza JL, Eng FJ, Carlson M (1989) Molecular analysis of the SNF4 gene of Saccharomyces cerevisiae: evidence for physical association of the SNF4 protein with the SNF1 protein kinase. Mol Cell Biol 9: 5045–5054. 2481228

57. Kanthakumar K, Taylor G, Tsang KW, Cundell DR, Rutman A, et al. (1993) Mechanisms of action of Pseudomonas aeruginosa pyocyanin on human ciliary beat in vitro. Infect Immun 61: 2848–2853. 8390405

58. Enloe B, Diamond A, Mitchell AP (2000) A single-transformation gene function test in diploid Candida albicans. J Bacteriol 182: 5730–5736. 11004171

59. Shapiro RS, Uppuluri P, Zaas AK, Collins C, Senn H, et al. (2009) Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA signaling. Curr Biol 19: 621–629. doi: 10.1016/j.cub.2009.03.017 19327993

60. Chautard H, Jacquet M, Schoentgen F, Bureaud N, Benedetti H (2004) Tfs1p, a member of the PEBP family, inhibits the Ira2p but not the Ira1p Ras GTPase-activating protein in Saccharomyces cerevisiae. Eukaryot Cell 3: 459–470. 15075275

61. Harashima T, Anderson S, Yates JR 3rd, Heitman J (2006) The kelch proteins Gpb1 and Gpb2 inhibit Ras activity via association with the yeast RasGAP neurofibromin homologs Ira1 and Ira2. Mol Cell 22: 819–830. 16793550

62. Aun A, Tamm T, Sedman J (2013) Dysfunctional mitochondria modulate cAMP-PKA signaling and filamentous and invasive growth of Saccharomyces cerevisiae. Genetics 193: 467–481. doi: 10.1534/genetics.112.147389 23172851

63. O'Meara TR, Veri AO, Ketela T, Jiang B, Roemer T, et al. (2015) Global analysis of fungal morphology exposes mechanisms of host cell escape. Nat Commun 6: 6741. doi: 10.1038/ncomms7741 25824284

64. Brooks GA, Hittelman KJ, Faulkner JA, Beyer RE (1971) Temperature, skeletal muscle mitochondrial functions, and oxygen debt. Am J Physiol 220: 1053–1059. 4323901

65. Dufour S, Rousse N, Canioni P, Diolez P (1996) Top-down control analysis of temperature effect on oxidative phosphorylation. Biochem J 314 (Pt 3): 743–751. 8615765

66. Ali SS, Marcondes MC, Bajova H, Dugan LL, Conti B (2010) Metabolic depression and increased reactive oxygen species production by isolated mitochondria at moderately lower temperatures. J Biol Chem 285: 32522–32528. doi: 10.1074/jbc.M110.155432 20716522

67. Swegert CV, Dave KR, Katyare SS (1999) Effect of aluminium-induced Alzheimer like condition on oxidative energy metabolism in rat liver, brain and heart mitochondria. Mech Ageing Dev 112: 27–42. 10656181

68. Morales DK, Jacobs NJ, Rajamani S, Krishnamurthy M, Cubillos-Ruiz JR, et al. (2010) Antifungal mechanisms by which a novel Pseudomonas aeruginosa phenazine toxin kills Candida albicans in biofilms. Mol Microbiol 78: 1379–1392. doi: 10.1111/j.1365-2958.2010.07414.x 21143312

69. Dietrich LE, Okegbe C, Price-Whelan A, Sakhtah H, Hunter RC, et al. (2013) Bacterial community morphogenesis is intimately linked to the intracellular redox state. J Bacteriol 195: 1371–1380. doi: 10.1128/JB.02273-12 23292774

70. Shin SY, Kim TH, Wu H, Choi YH, Kim SG (2014) SIRT1 activation by methylene blue, a repurposed drug, leads to AMPK-mediated inhibition of steatosis and steatohepatitis. Eur J Pharmacol 727: 115–124. doi: 10.1016/j.ejphar.2014.01.035 24486702

71. Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13: 1016–1023. doi: 10.1038/ncb2329 21892142

72. Vyas VK, Barrasa I, Fink GR (2015) A Candida albicans CRISPR system permits genetic engineering of essential genes and gene families. Science Advances 1.

73. Zhang F, Pracheil T, Thornton J, Liu Z (2013) Adenosine Triphosphate (ATP) Is a Candidate Signaling Molecule in the Mitochondria-to-Nucleus Retrograde Response Pathway. Genes (Basel) 4: 86–100.

74. Bao Y, Ledderose C, Seier T, Graf AF, Brix B, et al. (2014) Mitochondria regulate neutrophil activation by generating ATP for autocrine purinergic signaling. J Biol Chem 289: 26794–26803. doi: 10.1074/jbc.M114.572495 25104353

75. Burnstock G (2006) Historical review: ATP as a neurotransmitter. Trends Pharmacol Sci 27: 166–176. 16487603

76. Colombo S, Paiardi C, Pardons K, Winderickx J, Martegani E (2014) Evidence for adenylate cyclase as a scaffold protein for Ras2-Ira interaction in Saccharomyces cerevisie. Cell Signal 26: 1147–1154. doi: 10.1016/j.cellsig.2014.02.001 24518043

77. Hlavata L, Nystrom T (2003) Ras proteins control mitochondrial biogenesis and function in Saccharomyces cerevisiae. Folia Microbiol (Praha) 48: 725–730.

78. Belotti F, Tisi R, Paiardi C, Rigamonti M, Groppi S, et al. (2012) Localization of Ras signaling complex in budding yeast. Biochim Biophys Acta 1823: 1208–1216. doi: 10.1016/j.bbamcr.2012.04.016 22575457

79. Galello F, Moreno S, Rossi S (2014) Interacting proteins of protein kinase A regulatory subunit in Saccharomyces cerevisiae. J Proteomics 109: 261–275. doi: 10.1016/j.jprot.2014.07.008 25065647

80. Hall RA, De Sordi L, Maccallum DM, Topal H, Eaton R, et al. (2010) CO(2) acts as a signalling molecule in populations of the fungal pathogen Candida albicans. PLoS Pathog 6: e1001193. doi: 10.1371/journal.ppat.1001193 21124988

81. Xu XL, Lee RT, Fang HM, Wang YM, Li R, et al. (2008) Bacterial peptidoglycan triggers Candida albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p. Cell Host Microbe 4: 28–39. doi: 10.1016/j.chom.2008.05.014 18621008

82. Wilson RB, Davis D, Mitchell AP (1999) Rapid hypothesis testing with Candida albicans through gene disruption with short homology regions. J Bacteriol 181: 1868–1874. 10074081

83. Murad AM, Lee PR, Broadbent ID, Barelle CJ, Brown AJ (2000) CIp10, an efficient and convenient integrating vector for Candida albicans. Yeast 16: 325–327. 10669870

84. Miller L (2010) Analyzing gels and western blots with ImageJ.

85. Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, et al. (2008) Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol 26: 317–325. doi: 10.1038/nbt1385 18278033

86. Warnes GR, Bolker B, Bonebakker L, Gentleman R, Huber W, et al. (2014) R: A language and environment for statistical computing. 2.15.0 ed. Vienna, Austria: R Foundation for Statistical Computing.

87. Kestler HA, Muller A, Kraus JM, Buchholz M, Gress TM, et al. (2008) VennMaster: area-proportional Euler diagrams for functional GO analysis of microarrays. BMC Bioinformatics 9: 67. doi: 10.1186/1471-2105-9-67 18230172

88. Micallef L, Rodgers P (2014) eulerAPE: drawing area-proportional 3-Venn diagrams using ellipses. PLoS One 9: e101717. doi: 10.1371/journal.pone.0101717 25032825