A Single Nucleotide Polymorphism Uncovers a Novel Function for the Transcription Factor Ace2 during Hyphal Development

English version České info

Candida albicans is a major fungal pathogen in immunologically compromised patients. A key virulence trait is its ability to switch between the yeast and hyphal forms. Whereas yeast cells are required for dissemination, the filamentous forms are important in tissue penetration and invasion. In order to make a hypha, cell separation must be inhibited after cytokinesis, although the full extent of its regulation remains unknown. Previously, we have shown that the inhibition of cell separation in hyphae requires a modification of the dynamic properties of septins, a conserved family of GTPases that normally form a ring at the site of cytokinesis. Here we describe new factors regulating septin dynamics during hyphal development. We have discovered that an alternative translation initiation of ACE2 mRNAs gives rise to an Ace2 protein, Ace2L, with an extra 54 aa at the N-terminus that exhibits a localization and function different from Ace2 transcription factor. This Ace2L protein is upregulated upon hyphal induction and regulates the incorporation of the Sep7 septin into the septin rings to avoid inappropriate activation of cell separation in hyphae. Finally, we present evidence suggesting that the NDR kinase Cbk1 interacts with Ace2L to regulate this process.

Vyšlo v časopise: A Single Nucleotide Polymorphism Uncovers a Novel Function for the Transcription Factor Ace2 during Hyphal Development. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005152
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005152

Souhrn

Zdroje

1. Berman J, Sudbery PE. Candida albicans: a molecular revolution built on lessons from budding yeast. Nat Rev Genet. 2002;3 : 918–930. 12459722

2. Sudbery PE. Growth of Candida albicans hyphae. Nat Rev Microbiol. 2011;9 : 737–748. doi: 10.1038/nrmicro2636 21844880

3. Dohrmann PR, Butler G, Tamai K, Dorland S, Greene JR, Thiele DJ, et al. Parallel pathways of gene regulation: homologous regulators SWI5 and ACE2 differentially control transcription of HO and chitinase. Genes Dev. 1992;6 : 93–104. 1730413

4. Kelly MT, MacCallum DM, Clancy SD, Odds FC, Brown AJ, Butler G. The Candida albicans CaACE2 gene affects morphogenesis, adherence and virulence. Mol Microbiol. 2004;53 : 969–983. 15255906

5. Mulhern SM, Logue ME, Butler G. Candida albicans transcription factor Ace2 regulates metabolism and is required for filamentation in hypoxic conditions. Eukaryot Cell. 2006;5 : 2001–2013. 16998073

6. Saputo S, Chabrier-Rosello Y, Luca FC, Kumar A, Krysan DJ. The RAM network in pathogenic fungi. Eukaryot Cell. 2012;11 : 708–717. doi: 10.1128/EC.00044-12 22544903

7. Bidlingmaier S, Weiss EL, Seidel C, Drubin DG, Snyder M. The Cbk1p pathway is important for polarized cell growth and cell separation in Saccharomyces cerevisiae. Mol Cell Biol. 2001;21 : 2449–2462. 11259593

8. Colman-Lerner A, Chin TE, Brent R. Yeast Cbk1 and Mob2 activate daughter-specific genetic programs to induce asymmetric cell fates. Cell. 2001;107 : 739–750. 11747810

9. Nelson B, Kurischko C, Horecka J, Mody M, Nair P, Pratt L, et al. RAM: A conserved signaling network that regulates Ace2p transcriptional activity and polarized morphogenesis. Mol Biol Cell. 2003;14 : 3782–3803. 12972564

10. Racki WJ, Becam AM, Nasr F, Herbert CJ. Cbk1p, a protein similar to the human myotonic dystrophy kinase, is essential for normal morphogenesis in Saccharomyces cerevisiae. EMBO J. 2000;19 : 4524–4532. 10970846

11. Weiss EL, Kurischko C, Zhang C, Shokat K, Drubin DG, Luca FC. The Saccharomyces cerevisiae Mob2p-Cbk1p kinase complex promotes polarized growth and acts with the mitotic exit network to facilitate daughter cell-specific localization of Ace2p transcription factor. J Cell Biol. 2002;158 : 885–900. 12196508

12. O'Conallain C, Doolin MT, Taggart C, Thornton F, Butler G. Regulated nuclear localisation of the yeast transcription factor Ace2p controls expression of chitinase (CTS1) in Saccharomyces cerevisiae. Mol Gen Genet. 1999;262 : 275–222. 10517323

13. Baladrón V, Ufano S, Dueñas E, Martín-Cuadrado AB, del Rey F, Vázquez de Aldana CR. Eng1p, an endo-1,3-β-glucanase localized at the daughter side of the septum, is involved in cell separation in Saccharomyces cerevisiae. Eukaryot Cell. 2002;1 : 774–786. 12455695

14. Mazanka E, Alexander J, Yeh BJ, Charoenpong P, Lowery DM, Yaffe M, et al. The NDR/LATS family kinase Cbk1 directly controls transcriptional asymmetry. PLoS Biol. 2008;6: e203. doi: 10.1371/journal.pbio.0060203 18715118

15. Clemente-Blanco A, González-Novo A, Machín F, Caballero-Lima D, Aragón L, Sánchez M, et al. The Cdc14p phosphatase affects late cell-cycle events and morphogenesis in Candida albicans. J Cell Sci. 2006;119 : 1130–1143. 16507592

16. Song Y, Cheon SA, Lee KE, Lee SY, Lee BK, Oh DB, et al. Role of the RAM network in cell polarity and hyphal morphogenesis in Candida albicans. Mol Biol Cell. 2008;19 : 5456–5477. doi: 10.1091/mbc.E08-03-0272 18843050

17. Gutiérrez-Escribano P, González-Novo A, Suárez MB, Li CR, Wang Y, Vázquez de Aldana CR, et al. CDK-dependent phosphorylation of Mob2 is essential for hyphal development in Candida albicans. Mol Biol Cell. 2011;22 : 2458–2469. doi: 10.1091/mbc.E11-03-0205 21593210

18. Bertin A, Nogales E. Septin filament organization in Saccharomyces cerevisiae. Commun Integr Biol. 2012;5 : 503–505. doi: 10.4161/cib.21125 23739625

19. Oh Y, Bi E. Septin structure and function in yeast and beyond. Trends Cell Biol. 2011;21 : 141–148. doi: 10.1016/j.tcb.2010.11.006 21177106

20. Gladfelter AS. Guides to the final frontier of the cytoskeleton: septins in filamentous fungi. Curr Opin Microbiol. 2010;13 : 720–726. doi: 10.1016/j.mib.2010.09.012 20934902

21. González-Novo A, Vázquez de Aldana CR, Jiménez J. Fungal septins: one ring to rule it all? Cent Eur J Biol. 2009;4 : 274–289.

22. Weirich CS, Erzberger JP, Barral Y. The septin family of GTPases: architecture and dynamics. Nat Rev Mol Cell Biol. 2008;9 : 478–489. doi: 10.1038/nrm2407 18478031

23. Fung KY, Dai L, Trimble WS. Cell and molecular biology of septins. Int Rev Cell Mol Biol. 2014;310 : 289–339. doi: 10.1016/B978-0-12-800180-6.00007-4 24725429

24. Saarikangas J, Barral Y. The emerging functions of septins in metazoans. EMBO Rep. 2011;12 : 1118–1126. doi: 10.1038/embor.2011.193 21997296

25. Sirajuddin M, Farkasovsky M, Hauer F, Kuhlmann D, Macara IG, Weyand M, et al. Structural insight into filament formation by mammalian septins. Nature. 2007;449 : 311–315. 17637674

26. Hartwell LH. Genetic control of the cell division cycle in yeast. IV. Genes controlling bud emergence and cytokinesis. Exp Cell Res. 1971;69 : 265–276. 4950437

27. Mino A, Tanaka K, Kamei T, Umikawa M, Fujiwara T, Takai Y. Shs1p: a novel member of septin that interacts with Spa2p, involved in polarized growth in Saccharomyces cerevisiae. Biochem Biophys Res Commun. 1998;251 : 732–736. 9790978

28. Bertin A, McMurray MA, Grob P, Park SS, Garcia G 3rd, Patanwala I, et al. Saccharomyces cerevisiae septins: supramolecular organization of heterooligomers and the mechanism of filament assembly. Proc Natl Acad Sci USA. 2008;105 : 8274–8279. doi: 10.1073/pnas.0803330105 18550837

29. Gladfelter AS, Kozubowski L, Zyla TR, Lew DJ. Interplay between septin organization, cell cycle and cell shape in yeast. J Cell Sci. 2005;118 : 1617–1628. 15784684

30. Cid VJ, Adamikova L, Sanchez M, Molina M, Nombela C. Cell cycle control of septin ring dynamics in the budding yeast. Microbiology. 2001;147 : 1437–1450. 11390675

31. Sudbery PE. The germ tubes of Candida albicans hyphae and pseudohyphae show different patterns of septin ring localization. Mol Microbiol. 2001;41 : 19–31. 11454197

32. Warenda AJ, Konopka JB. Septin function in Candida albicans morphogenesis. Mol Biol Cell. 2002;13 : 2732–2746. 12181342

33. González-Novo A, Correa-Bordes J, Labrador L, Sánchez M, Vázquez de Aldana CR, Jiménez J. Sep7 is essential to modify septin ring dynamics and inhibit cell separation during Candida albicans hyphal growth. Mol Biol Cell. 2008;19 : 1509–1518. doi: 10.1091/mbc.E07-09-0876 18234840

34. Dunkler A, Walther A, Specht CA, Wendland J. Candida albicans CHT3 encodes the functional homolog of the Cts1 chitinase of Saccharomyces cerevisiae. Fungal Genet Biol. 2005;42 : 935–947. 16214381

35. Esteban PF, Ríos I, García R, Dueñas E, Plá J, Sánchez M, et al. Characterization of the CaENG1 gene encoding an endo-1,3-β-glucanase involved in cell separation in Candida albicans. Curr Microbiol. 2005;51 : 385–392. 16328626

36. Jones T, Federspiel NA, Chibana H, Dungan J, Kalman S, Magee BB, et al. The diploid genome sequence of Candida albicans. Proc Natl Acad Sci USA. 2004;101 : 7329–7334. 15123810

37. Inglis DO, Arnaud MB, Binkley J, Shah P, Skrzypek MS, Wymore F, et al. The Candida genome database incorporates multiple Candida species: multispecies search and analysis tools with curated gene and protein information for Candida albicans and Candida glabrata. Nucleic Acids Res. 2012;40: D667–674. doi: 10.1093/nar/gkr945 22064862

38. Goodwin TJ, Poulter RT. Multiple LTR-retrotransposon families in the asexual yeast Candida albicans. Genome Res. 2000;10 : 174–191. 10673276

39. Wang A, Raniga PP, Lane S, Lu Y, Liu H. Hyphal chain formation in Candida albicans: Cdc28-Hgc1 phosphorylation of Efg1 represses cell separation genes. Mol Cell Biol. 2009;29 : 4406–4416. doi: 10.1128/MCB.01502-08 19528234

40. Slutsky B, Staebell M, Anderson J, Risen L, Pfaller M, Soll DR. "White-opaque transition": a second high-frequency switching system in Candida albicans. J Bacteriol. 1987;169 : 189–197. 3539914

41. Butler G, Rasmussen MD, Lin MF, Santos MA, Sakthikumar S, Munro CA, et al. Evolution of pathogenicity and sexual reproduction in eight Candida genomes. Nature. 2009;459 : 657–662. doi: 10.1038/nature08064 19465905

42. Si H, Hernday AD, Hirakawa MP, Johnson AD, Bennett RJ. Candida albicans white and opaque cells undergo distinct programs of filamentous growth. PLoS pathog. 2013;9: e1003210. doi: 10.1371/journal.ppat.1003210 23505370

43. Crampin H, Finley K, Gerami-Nejad M, Court H, Gale C, Berman J, et al. Candida albicans hyphae have a Spitzenkorper that is distinct from the polarisome found in yeast and pseudohyphae. J Cell Sci. 2005;118 : 2935–2947. 15976451

44. Care RS, Trevethick J, Binley KM, Sudbery PE. The MET3 promoter: a new tool for Candida albicans molecular genetics. Mol Microbiol. 1999;34 : 792–798. 10564518

45. McBride HJ, Yu Y, Stillman DJ. Distinct regions of the Swi5 and Ace2 transcription factors are required for specific gene activation. J Biol Chem. 1999;274 : 21029–21036. 10409653

46. Sbia M, Parnell EJ, Yu Y, Olsen AE, Kretschmann KL, Voth WP, et al. Regulation of the yeast Ace2 transcription factor during the cell cycle. J Biol Chem. 2008;283 : 11135–11145. doi: 10.1074/jbc.M800196200 18292088

47. Brace J, Hsu J, Weiss EL. Mitotic exit control of the Saccharomyces cerevisiae Ndr/LATS kinase Cbk1 regulates daughter cell separation after cytokinesis. Mol Cell Biol. 2011;31 : 721–735. doi: 10.1128/MCB.00403-10 21135117

48. Alonso-Núñez ML, An H, Martín-Cuadrado AB, Mehta S, Petit C, Sipiczki M, et al. Ace2p controls the expression of genes required for cell separation in Schizosaccharomyces pombe. Mol Biol Cell. 2005;16 : 2003–2017. 15689498

49. Spellman PT, Sherlock G, Zhang MQ, Iyer VR, Anders K, Eisen MB, et al. Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol Biol Cell. 1998;9 : 3273–3297. 9843569

50. Martín-Cuadrado AB, Dueñas E, Sipiczki M, Vázquez de Aldana CR, del Rey F. The endo-β-1,3-glucanase Eng1p is required for dissolution of the primary septum during cell separation in Schizosaccharomyces pombe. J Cell Sci. 2003;116 : 1689–1698. 12665550

51. Li CR, Lee RT, Wang YM, Zheng XD, Wang Y. Candida albicans hyphal morphogenesis occurs in Sec3p-independent and Sec3p-dependent phases separated by septin ring formation. J Cell Sci. 2007;120 : 1898–1907. 17504812

52. Sudbery P. Morphogenesis of a human fungal pathogen requires septin phosphorylation. Dev Cell. 2007;13 : 315–316. 17765672

53. Garcia G 3rd, Bertin A, Li Z, Song Y, McMurray MA, Thorner J, et al. Subunit-dependent modulation of septin assembly: budding yeast septin Shs1 promotes ring and gauze formation. J Cell Biol. 2011;195 : 993–1004. doi: 10.1083/jcb.201107123 22144691

54. Odds FC, Bougnoux ME, Shaw DJ, Bain JM, Davidson AD, Diogo D, et al. Molecular phylogenetics of Candida albicans. Eukaryot Cell. 2007;6 : 1041–1052. 17416899

55. McManus BA, Coleman DC. Molecular epidemiology, phylogeny and evolution of Candida albicans. Infect Genet Evol. 2014;21 : 166–178. doi: 10.1016/j.meegid.2013.11.008 24269341

56. Schmid J, Herd S, Hunter PR, Cannon RD, Yasin MS, Samad S, et al. Evidence for a general-purpose genotype in Candida albicans, highly prevalent in multiple geographical regions, patient types and types of infection. Microbiology. 1999;145 : 2405–2413. 10517593

57. Odds FC. Molecular phylogenetics and epidemiology of Candida albicans. Future Microbiol. 2010;5 : 67–79. doi: 10.2217/fmb.09.113 20020830

58. Forche A, Magee PT, Selmecki A, Berman J, May G. Evolution in Candida albicans populations during a single passage through a mouse host. Genetics. 2009;182 : 799–811. doi: 10.1534/genetics.109.103325 19414562

59. Forche A, Abbey D, Pisithkul T, Weinzierl MA, Ringstrom T, Bruck D, et al. Stress alters rates and types of loss of heterozygosity in Candida albicans. MBio. 2011;2: e00129–00111. doi: 10.1128/mBio.00129-11 21791579

60. Gola S, Martin R, Walther A, Dunkler A, Wendland J. New modules for PCR-based gene targeting in Candida albicans: rapid and efficient gene targeting using 100 bp of flanking homology region. Yeast. 2003;20 : 1339–1347. 14663826

61. Schaub Y, Dunkler A, Walther A, Wendland J. New pFA-cassettes for PCR-based gene manipulation in Candida albicans. J Basic Microbiol. 2006;46 : 416–429. 17009297

62. Reijnst P, Walther A, Wendland J. Dual-colour fluorescence microscopy using yEmCherry-/GFP-tagging of eisosome components Pil1 and Lsp1 in Candida albicans. Yeast. 2011;28 : 331–338. doi: 10.1002/yea.1841 21312263

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

64. Gutiérrez-Escribano P, Zeidler U, Suárez MB, Bachellier-Bassi S, Clemente-Blanco A, Bonhomme J, et al. The NDR/LATS kinase Cbk1 controls the activity of the transcriptional regulator Bcr1 during biofilm formation in Candida albicans. PLoS pathog. 2012;8: e1002683. doi: 10.1371/journal.ppat.1002683 22589718