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Control of Candida albicans morphology and pathogenicity by post-transcriptional mechanisms

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Abstract

Candida albicans is a major human fungal pathogen responsible for both systemic and mucosal infections in a wide variety of immunocompromised individuals. Because the ability of C. albicans to undergo a reversible morphological transition from yeast to filaments is important for virulence, significant research efforts have focused on mechanisms that control this transition. While transcriptional and post-translational mechanisms have been well-studied, considerably less is known about the role of post-transcriptional mechanisms. However, in recent years several discoveries have begun to shed light on this important, but understudied, area. Here, I will review a variety of post-transcriptional mechanisms that have recently been shown to control C. albicans morphology, virulence and/or virulence-related processes, including those involving alternative transcript localization, mRNA stability and translation. I will also discuss the role that these mechanisms play in other pathogens as well as the potential they may hold to serve as targets for new antifungal strategies. Ultimately, gaining a better understanding of C. albicans post-transcriptional mechanisms will significantly improve our knowledge of how morphogenesis and virulence are controlled in fungal pathogens and open new avenues for the development of novel and more effective antifungals.

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References

  1. Odds FC (1988) Candida and Candidosis, 2nd edn. Baillière Tindall, London

    Google Scholar 

  2. Odds FC (1994) Candida species and virulence. ASM News 60(6):313–318

    Google Scholar 

  3. Odds FC (1994) Pathogenesis of Candida infections. J Am Acad Dermatol 31(3 Pt 2):S2–S5

    Article  CAS  PubMed  Google Scholar 

  4. Dupont PF (1995) Candida albicans, the opportunist. A cellular and molecular perspective. J Am Podiatr Med Assoc 85(2):104–115

    Article  CAS  PubMed  Google Scholar 

  5. Weig M, Gross U, Muhlschlegel F (1998) Clinical aspects and pathogenesis of Candida infection. Trends Microbiol 6(12):468–470

    Article  CAS  PubMed  Google Scholar 

  6. Fidel PL Jr, Vazquez JA, Sobel JD (1999) Candida glabrata: review of epidemiology, pathogenesis, and clinical disease with comparison to C. albicans. Clin Microbiol Rev 12(1):80–96

    PubMed  PubMed Central  Google Scholar 

  7. Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP (1999) Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis 29(2):239–244

    Article  CAS  PubMed  Google Scholar 

  8. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39(3):309–317. doi:10.1086/421946CID32752

    Article  PubMed  Google Scholar 

  9. Shepherd MG, Poulter RT, Sullivan PA (1985) Candida albicans: biology, genetics, and pathogenicity. Annu Rev Microbiol 39:579–614

    Article  CAS  PubMed  Google Scholar 

  10. Miller LG, Hajjeh RA, Edwards JE Jr (2001) Estimating the cost of nosocomial candidemia in the United States. Clin Infect Dis 32(7):1110

    Article  CAS  PubMed  Google Scholar 

  11. Odds FC, Brown AJ, Gow NA (2003) Antifungal agents: mechanisms of action. Trends Microbiol 11(6):272–279

    Article  CAS  PubMed  Google Scholar 

  12. Xie JL, Polvi EJ, Shekhar-Guturja T, Cowen LE (2014) Elucidating drug resistance in human fungal pathogens. Future Microbiol 9(4):523–542. doi:10.2217/fmb.14.18

    Article  CAS  PubMed  Google Scholar 

  13. Brown DH Jr, Giusani AD, Chen X, Kumamoto CA (1999) Filamentous growth of Candida albicans in response to physical environmental cues and its regulation by the unique CZF1 gene. Mol Microbiol 34(4):651–662

    Article  CAS  PubMed  Google Scholar 

  14. Brown AJ (2002) Morphogenetic signaling pathways in Candida albicans. In: Calderone RA (ed) Candida and Candidiasis. ASM Press, Washington, D.C., pp 95–106

    Google Scholar 

  15. Calderone RA, Fonzi WA (2001) Virulence factors of Candida albicans. Trends Microbiol 9(7):327–335

    Article  CAS  PubMed  Google Scholar 

  16. Calderone RA, Gow NA (2002) Host recognition by Candida species. In: Calderone RA (ed) Candida and Candidiasis. ASM Press, Washington, D.C., pp 67–86

    Google Scholar 

  17. Ernst JF (2000) Transcription factors in Candida albicans - environmental control of morphogenesis. Microbiology 146(Pt 8):1763–1774

    Article  CAS  PubMed  Google Scholar 

  18. Ernst JF (2000) Regulation of dimorphism in Candida albicans. Contrib Microbiol 5:98–111

    Article  CAS  PubMed  Google Scholar 

  19. Lo HJ, Kohler JR, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink GR (1997) Nonfilamentous C. albicans mutants are avirulent. Cell 90(5):939–949

    Article  CAS  PubMed  Google Scholar 

  20. Mitchell AP (1998) Dimorphism and virulence in Candida albicans. Curr Opin Microbiol 1(6):687–692

    Article  CAS  PubMed  Google Scholar 

  21. 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(5):1053–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Odds FC (1985) Morphogenesis in Candida albicans. Crit Rev Microbiol 12(1):45–93

    Article  CAS  PubMed  Google Scholar 

  23. Sudbery P, Gow N, Berman J (2004) The distinct morphogenic states of Candida albicans. Trends Microbiol 12(7):317–324

    Article  CAS  PubMed  Google Scholar 

  24. Erwig LP, Gow NA (2016) Interactions of fungal pathogens with phagocytes. Nat Rev Microbiol 14(3):163–176. doi:10.1038/nrmicro.2015.21

    Article  CAS  PubMed  Google Scholar 

  25. Brown AJ, Gow NA (1999) Regulatory networks controlling Candida albicans morphogenesis. Trends Microbiol 7(8):333–338

    Article  CAS  PubMed  Google Scholar 

  26. Biswas S, Van Dijck P, Datta A (2007) Environmental sensing and signal transduction pathways regulating morphopathogenic determinants of Candida albicans. Microbiol Mol Biol Rev 71(2):348–376. doi:10.1128/MMBR.00009-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kumamoto CA, Vinces MD (2005) Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence. Cell Microbiol 7(11):1546–1554

    Article  CAS  PubMed  Google Scholar 

  28. Korting HC, Hube B, Oberbauer S, Januschke E, Hamm G, Albrecht A, Borelli C, Schaller M (2003) Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium. J Med Microbiol 52(Pt 8):623–632

    Article  CAS  PubMed  Google Scholar 

  29. Gow NA, Brown AJ, Odds FC (2002) Fungal morphogenesis and host invasion. Curr Opin Microbiol 5(4):366–371

    Article  CAS  PubMed  Google Scholar 

  30. Braun BR, Johnson AD (1997) Control of filament formation in Candida albicans by the transcriptional repressor TUP1. Science 277(5322):105–109

    Article  CAS  PubMed  Google Scholar 

  31. Braun BR, Head WS, Wang MX, Johnson AD (2000) Identification and characterization of TUP1-regulated genes in Candida albicans. Genetics 156(1):31–44

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Carlisle PL, Banerjee M, Lazzell A, Monteagudo C, Lopez-Ribot JL, Kadosh D (2009) Expression levels of a filament-specific transcriptional regulator are sufficient to determine Candida albicans morphology and virulence. Proc Natl Acad Sci USA 106:599–604

    Article  CAS  PubMed  Google Scholar 

  33. Noble SM, French S, Kohn LA, Chen V, Johnson AD (2010) Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity. Nat Genet 42(7):590–598. doi:10.1038/ng.605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sudbery PE (2011) Growth of Candida albicans hyphae. Nat Rev Microbiol 9(10):737–748. doi:10.1038/nrmicro2636

    Article  CAS  PubMed  Google Scholar 

  35. Song Y, Cheon SA, Lee KE, Lee SY, Lee BK, Oh DB, Kang HA, Kim JY (2008) Role of the RAM network in cell polarity and hyphal morphogenesis in Candida albicans. Mol Biol Cell 19(12):5456–5477. doi:10.1091/mbc.E08-03-0272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang Y (2009) CDKs and the yeast-hyphal decision. Curr Opin Microbiol 12(6):644–649. doi:10.1016/j.mib.2009.09.002

    Article  CAS  PubMed  Google Scholar 

  37. Lopes da Rosa J, Kaufman PD (2012) Chromatin-mediated Candida albicans virulence. Biochim Biophys Acta 1819(3–4):349–355. doi:10.1016/j.bbagrm.2011.08.007

    Article  CAS  PubMed  Google Scholar 

  38. Hnisz D, Majer O, Frohner IE, Komnenovic V, Kuchler K (2010) The Set3/Hos2 histone deacetylase complex attenuates cAMP/PKA signaling to regulate morphogenesis and virulence of Candida albicans. PLoS Pathog 6(5):e1000889. doi:10.1371/journal.ppat.1000889

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lopes da Rosa J, Boyartchuk VL, Zhu LJ, Kaufman PD (2010) Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis. Proc Natl Acad Sci USA 107(4):1594–1599. doi:10.1073/pnas.0912427107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Leach MD, Stead DA, Argo E, MacCallum DM, Brown AJ (2011) Molecular and proteomic analyses highlight the importance of ubiquitination for the stress resistance, metabolic adaptation, morphogenetic regulation and virulence of Candida albicans. Mol Microbiol 79(6):1574–1593. doi:10.1111/j.1365-2958.2011.07542.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Leach MD, Stead DA, Argo E, Brown AJ (2011) Identification of sumoylation targets, combined with inactivation of SMT3, reveals the impact of sumoylation upon growth, morphology, and stress resistance in the pathogen Candida albicans. Mol Biol Cell 22(5):687–702. doi:10.1091/mbc.E10-07-0632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Leach MD, Brown AJ (2012) Posttranslational modifications of proteins in the pathobiology of medically relevant fungi. Eukaryot Cell 11(2):98–108. doi:10.1128/EC.05238-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Calderone RA, Clancy CJ (eds) (2012) Candida and Candidiasis, 2nd edn. ASM Press, Washington, D.C

    Google Scholar 

  44. Lu Y, Su C, Wang A, Liu H (2011) Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance. PLoS Biol 9(7):e1001105. doi:10.1371/journal.pbio.1001105PBIOLOGY-D-10-01188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Felk A, Kretschmar M, Albrecht A, Schaller M, Beinhauer S, Nichterlein T, Sanglard D, Korting HC, Schafer W, Hube B (2002) Candida albicans hyphal formation and the expression of the Efg1-regulated proteinases Sap4 to Sap6 are required for the invasion of parenchymal organs. Infect Immun 70(7):3689–3700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sohn K, Urban C, Brunner H, Rupp S (2003) EFG1 is a major regulator of cell wall dynamics in Candida albicans as revealed by DNA microarrays. Mol Microbiol 47(1):89–102

    Article  CAS  PubMed  Google Scholar 

  47. Kadosh D, Johnson AD (2005) Induction of the Candida albicans filamentous growth program by relief of transcriptional repression: a genome-wide analysis. Mol Biol Cell 16(6):2903–2912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sellam A, Tebbji F, Whiteway M, Nantel A (2012) A novel role for the transcription factor Cwt1p as a negative regulator of nitrosative stress in Candida albicans. PLoS One 7(8):e43956. doi:10.1371/journal.pone.0043956PONE-D-12-11874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chen C, Pande K, French SD, Tuch BB, Noble SM (2011) An iron homeostasis regulatory circuit with reciprocal roles in Candida albicans commensalism and pathogenesis. Cell Host Microbe 10(2):118–135. doi:10.1016/j.chom.2011.07.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zordan RE, Miller MG, Galgoczy DJ, Tuch BB, Johnson AD (2007) Interlocking transcriptional feedback loops control white-opaque switching in Candida albicans. PLoS Biol 5(10):e256. doi:10.1371/journal.pbio.0050256

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Nobile CJ, Fox EP, Nett JE, Sorrells TR, Mitrovich QM, Hernday AD, Tuch BB, Andes DR, Johnson AD (2012) A recently evolved transcriptional network controls biofilm development in Candida albicans. Cell 148(1–2):126–138. doi:10.1016/j.cell.2011.10.048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sanglard D, Coste A, Ferrari S (2009) Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation. FEMS Yeast Res 9(7):1029–1050. doi:10.1111/j.1567-1364.2009.00578.x

    Article  CAS  PubMed  Google Scholar 

  53. Verma-Gaur J, Traven A (2016) Post-transcriptional gene regulation in the biology and virulence of Candida albicans. Cell Microbiol 18(6):800–806. doi:10.1111/cmi.12593

    Article  CAS  PubMed  Google Scholar 

  54. Johnstone O, Lasko P (2001) Translational regulation and RNA localization in Drosophila oocytes and embryos. Annu Rev Genet 35:365–406. doi:10.1146/annurev.genet.35.102401.090756

    Article  CAS  PubMed  Google Scholar 

  55. King ML, Messitt TJ, Mowry KL (2005) Putting RNAs in the right place at the right time: RNA localization in the frog oocyte. Biol Cell 97(1):19–33. doi:10.1042/BC20040067

    Article  CAS  PubMed  Google Scholar 

  56. Lawrence JB, Singer RH (1986) Intracellular localization of messenger RNAs for cytoskeletal proteins. Cell 45(3):407–415

    Article  CAS  PubMed  Google Scholar 

  57. Eberwine J, Miyashiro K, Kacharmina JE, Job C (2001) Local translation of classes of mRNAs that are targeted to neuronal dendrites. Proc Natl Acad Sci USA 98(13):7080–7085. doi:10.1073/pnas.121146698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Takizawa PA, DeRisi JL, Wilhelm JE, Vale RD (2000) Plasma membrane compartmentalization in yeast by messenger RNA transport and a septin diffusion barrier. Science 290(5490):341–344

    Article  CAS  PubMed  Google Scholar 

  59. Shepard KA, Gerber AP, Jambhekar A, Takizawa PA, Brown PO, Herschlag D, DeRisi JL, Vale RD (2003) Widespread cytoplasmic mRNA transport in yeast: identification of 22 bud-localized transcripts using DNA microarray analysis. Proc Natl Acad Sci USA 100(20):11429–11434. doi:10.1073/pnas.2033246100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jansen RP, Dowzer C, Michaelis C, Galova M, Nasmyth K (1996) Mother cell-specific HO expression in budding yeast depends on the unconventional myosin myo4p and other cytoplasmic proteins. Cell 84(5):687–697

    Article  CAS  PubMed  Google Scholar 

  61. Munchow S, Sauter C, Jansen RP (1999) Association of the class V myosin Myo4p with a localised messenger RNA in budding yeast depends on She proteins. J Cell Sci 112(Pt 10):1511–1518

    CAS  PubMed  Google Scholar 

  62. Takizawa PA, Vale RD (2000) The myosin motor, Myo4p, binds Ash1 mRNA via the adapter protein, She3p. Proc Natl Acad Sci USA 97(10):5273–5278. doi:10.1073/pnas.080585897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Long RM, Gu W, Lorimer E, Singer RH, Chartrand P (2000) She2p is a novel RNA-binding protein that recruits the Myo4p-She3p complex to ASH1 mRNA. EMBO J 19(23):6592–6601. doi:10.1093/emboj/19.23.6592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bohl F, Kruse C, Frank A, Ferring D, Jansen RP (2000) She2p, a novel RNA-binding protein tethers ASH1 mRNA to the Myo4p myosin motor via She3p. EMBO J 19(20):5514–5524. doi:10.1093/emboj/19.20.5514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Takizawa PA, Sil A, Swedlow JR, Herskowitz I, Vale RD (1997) Actin-dependent localization of an RNA encoding a cell-fate determinant in yeast. Nature 389(6646):90–93. doi:10.1038/38015

    Article  CAS  PubMed  Google Scholar 

  66. Sil A, Herskowitz I (1996) Identification of asymmetrically localized determinant, Ash1p, required for lineage-specific transcription of the yeast HO gene. Cell 84(5):711–722

    Article  CAS  PubMed  Google Scholar 

  67. Elson SL, Noble SM, Solis NV, Filler SG, Johnson AD (2009) An RNA transport system in Candida albicans regulates hyphal morphology and invasive growth. PLoS Genet 5(9):e1000664. doi:10.1371/journal.pgen.1000664

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Steinberg G (2007) Hyphal growth: a tale of motors, lipids, and the Spitzenkorper. Eukaryot Cell 6(3):351–360. doi:10.1128/EC.00381-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Caballero-Lima D, Hautbergue GM, Wilson SA, Sudbery PE (2014) In Candida albicans hyphae, Sec2p is physically associated with SEC2 mRNA on secretory vesicles. Mol Microbiol 94(4):828–842. doi:10.1111/mmi.12799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bishop A, Lane R, Beniston R, Chapa-y-Lazo B, Smythe C, Sudbery P (2010) Hyphal growth in Candida albicans requires the phosphorylation of Sec2 by the Cdc28-Ccn1/Hgc1 kinase. EMBO J 29(17):2930–2942. doi:10.1038/emboj.2010.158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Newbury SF (2006) Control of mRNA stability in eukaryotes. Biochem Soc Trans 34(Pt 1):30–34. doi:10.1042/BST20060030

    Article  CAS  PubMed  Google Scholar 

  72. Cooperstock RL, Lipshitz HD (1997) Control of mRNA stability and translation during Drosophila development. Semin Cell Dev Biol 8(6):541–549. doi:10.1006/scdb.1997.0179

    Article  CAS  PubMed  Google Scholar 

  73. Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, Baillie DL, Fire A, Ruvkun G, Mello CC (2001) Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106(1):23–34

    Article  CAS  PubMed  Google Scholar 

  74. Gutierrez RA, Ewing RM, Cherry JM, Green PJ (2002) Identification of unstable transcripts in Arabidopsis by cDNA microarray analysis: rapid decay is associated with a group of touch- and specific clock-controlled genes. Proc Natl Acad Sci USA 99(17):11513–11518. doi:10.1073/pnas.152204099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Dagley MJ, Gentle IE, Beilharz TH, Pettolino FA, Djordjevic JT, Lo TL, Uwamahoro N, Rupasinghe T, Tull DL, McConville M, Beaurepaire C, Nantel A, Lithgow T, Mitchell AP, Traven A (2011) Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4–Pop2. Mol Microbiol 79(4):968–989. doi:10.1111/j.1365-2958.2010.07503.x

    Article  CAS  PubMed  Google Scholar 

  76. Lee KH, Kim SY, Jung JH, Kim J (2010) Proteomic analysis of hyphae-specific proteins that are expressed differentially in cakem1/cakem1 mutant strains of Candida albicans. J Microbiol 48(3):365–371. doi:10.1007/s12275-010-9155-4

    Article  PubMed  CAS  Google Scholar 

  77. An HS, Lee KH, Kim J (2004) Identification of an exoribonuclease homolog, CaKEM1/CaXRN1, in Candida albicans and its characterization in filamentous growth. FEMS Microbiol Lett 235(2):297–303. doi:10.1016/j.femsle.2004.04.048

    Article  CAS  PubMed  Google Scholar 

  78. Jung JH, Kim J (2011) Accumulation of P-bodies in Candida albicans under different stress and filamentous growth conditions. Fungal Genet Biol 48(12):1116–1123. doi:10.1016/j.fgb.2011.10.003

    Article  CAS  PubMed  Google Scholar 

  79. Shively CA, Kweon HK, Norman KL, Mellacheruvu D, Xu T, Sheidy DT, Dobry CJ, Sabath I, Cosky EE, Tran EJ, Nesvizhskii A, Andrews PC, Kumar A (2015) Large-scale analysis of kinase signaling in yeast pseudohyphal development identifies regulation of ribonucleoprotein granules. PLoS Genet 11(10):e1005564. doi:10.1371/journal.pgen.1005564

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Verma-Gaur J, Qu Y, Harrison PF, Lo TL, Quenault T, Dagley MJ, Bellousoff M, Powell DR, Beilharz TH, Traven A (2015) Integration of posttranscriptional gene networks into metabolic adaptation and biofilm maturation in Candida albicans. PLoS Genet 11(10):e1005590. doi:10.1371/journal.pgen.1005590

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Prasad R, De Wergifosse P, Goffeau A, Balzi E (1995) Molecular cloning and characterization of a novel gene of Candida albicans, CDR1, conferring multiple resistance to drugs and antifungals. Curr Genet 27(4):320–329

    Article  CAS  PubMed  Google Scholar 

  82. Manoharlal R, Gaur NA, Panwar SL, Morschhauser J, Prasad R (2008) Transcriptional activation and increased mRNA stability contribute to overexpression of CDR1 in azole-resistant Candida albicans. Antimicrob Agents Chemother 52(4):1481–1492. doi:10.1128/AAC.01106-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Manoharlal R, Gorantala J, Sharma M, Sanglard D, Prasad R (2010) PAP1 [poly(A) polymerase 1] homozygosity and hyperadenylation are major determinants of increased mRNA stability of CDR1 in azole-resistant clinical isolates of Candida albicans. Microbiology 156(Pt 2):313–326. doi:10.1099/mic.0.035154-0

    Article  CAS  PubMed  Google Scholar 

  84. Wells ML, Washington OL, Hicks SN, Nobile CJ, Hartooni N, Wilson GM, Zucconi BE, Huang W, Li L, Fargo DC, Blackshear PJ (2015) Post-transcriptional regulation of transcript abundance by a conserved member of the tristetraprolin family in Candida albicans. Mol Microbiol 95(6):1036–1053. doi:10.1111/mmi.12913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fabian MR, Frank F, Rouya C, Siddiqui N, Lai WS, Karetnikov A, Blackshear PJ, Nagar B, Sonenberg N (2013) Structural basis for the recruitment of the human CCR4-NOT deadenylase complex by tristetraprolin. Nat Struct Mol Biol 20(6):735–739. doi:10.1038/nsmb.2572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sandler H, Kreth J, Timmers HT, Stoecklin G (2011) Not1 mediates recruitment of the deadenylase Caf1 to mRNAs targeted for degradation by tristetraprolin. Nucleic Acids Res 39(10):4373–4386. doi:10.1093/nar/gkr011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jensen-Pergakes KL, Kennedy MA, Lees ND, Barbuch R, Koegel C, Bard M (1998) Sequencing, disruption, and characterization of the Candida albicans sterol methyltransferase (ERG6) gene: drug susceptibility studies in erg6 mutants. Antimicrob Agents Chemother 42(5):1160–1167

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ariyachet C, Solis NV, Liu Y, Prasadarao NV, Filler SG, McBride AE (2013) SR-like RNA-binding protein Slr1 affects Candida albicans filamentation and virulence. Infect Immun 81(4):1267–1276. doi:10.1128/IAI.00864-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ni L, Snyder M (2001) A genomic study of the bipolar bud site selection pattern in Saccharomyces cerevisiae. Mol Biol Cell 12(7):2147–2170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Mosch HU, Fink GR (1997) Dissection of filamentous growth by transposon mutagenesis in Saccharomyces cerevisiae. Genetics 145(3):671–684

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Shaw BD, Upadhyay S (2005) Aspergillus nidulans swoK encodes an RNA binding protein that is important for cell polarity. Fungal Genet Biol 42(10):862–872. doi:10.1016/j.fgb.2005.06.002

    Article  CAS  PubMed  Google Scholar 

  92. Cleary IA, Lazzell AL, Monteagudo C, Thomas DP, Saville SP (2012) BRG1 and NRG1 form a novel feedback circuit regulating Candida albicans hypha formation and virulence. Mol Microbiol 85(3):557–573. doi:10.1111/j.1365-2958.2012.08127.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Murad AMA, Leng P, Straffon M, Wishart J, Macaskill S, MacCallum D, Schnell N, Talibi D, Marechal D, Tekaia F, d’Enfert C, Gaillardin C, Odds FC, Brown AJP (2001) NRG1 represses yeast-hypha morphogenesis and hypha-specific gene expression in Candida albicans. EMBO J 20:4742–4752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Braun BR, Kadosh D, Johnson AD (2001) NRG1, a repressor of filamentous growth in C. albicans, is down-regulated during filament induction. EMBO J 20:4753–4761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Pickering BM, Willis AE (2005) The implications of structured 5′ untranslated regions on translation and disease. Semin Cell Dev Biol 16(1):39–47. doi:10.1016/j.semcdb.2004.11.006

    Article  CAS  PubMed  Google Scholar 

  96. Mignone F, Gissi C, Liuni S, Pesole G (2002) Untranslated regions of mRNAs. Genome Biol 3 (3):REVIEWS0004

  97. Hinnebusch AG, Natarajan K (2002) Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryot Cell 1(1):22–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tripathi G, Wiltshire C, Macaskill S, Tournu H, Budge S, Brown AJ (2002) Gcn4 co-ordinates morphogenetic and metabolic responses to amino acid starvation in Candida albicans. EMBO J 21(20):5448–5456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Garcia-Sanchez S, Aubert S, Iraqui I, Janbon G, Ghigo JM, d’Enfert C (2004) Candida albicans biofilms: a developmental state associated with specific and stable gene expression patterns. Eukaryot Cell 3(2):536–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sundaram A, Grant CM (2014) A single inhibitory upstream open reading frame (uORF) is sufficient to regulate Candida albicans GCN4 translation in response to amino acid starvation conditions. RNA 20(4):559–567. doi:10.1261/rna.042267.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sundaram A, Grant CM (2014) Oxidant-specific regulation of protein synthesis in Candida albicans. Fungal Genet Biol 67:15–23. doi:10.1016/j.fgb.2014.03.005

    Article  CAS  PubMed  Google Scholar 

  102. Banerjee M, Thompson DS, Lazzell A, Carlisle PL, Pierce C, Monteagudo C, Lopez-Ribot JL, Kadosh D (2008) UME6, a novel filament-specific regulator of Candida albicans hyphal extension and virulence. Mol Biol Cell 19(4):1354–1365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zeidler U, Lettner T, Lassnig C, Muller M, Lajko R, Hintner H, Breitenbach M, Bito A (2009) UME6 is a crucial downstream target of other transcriptional regulators of true hyphal development in Candida albicans. FEMS Yeast Res 9(1):126–142. doi:10.1111/j.1567-1364.2008.00459.x

    Article  CAS  PubMed  Google Scholar 

  104. Banerjee M, Uppuluri P, Zhao XR, Carlisle PL, Vipulanandan G, Villar CC, Lopez-Ribot JL, Kadosh D (2013) Expression of UME6, a key regulator of Candida albicans hyphal development, enhances biofilm formation via Hgc1- and Sun41-dependent mechanisms. Eukaryot Cell 12(2):224–232. doi:10.1128/EC.00163-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Childers DS, Mundodi V, Banerjee M, Kadosh D (2014) A 5′ UTR-mediated translational efficiency mechanism inhibits the Candida albicans morphological transition. Mol Microbiol 92(3):570–585. doi:10.1111/mmi.12576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zordan RE, Galgoczy DJ, Johnson AD (2006) Epigenetic properties of white-opaque switching in Candida albicans are based on a self-sustaining transcriptional feedback loop. Proc Natl Acad Sci USA 103(34):12807–12812. doi:10.1073/pnas.0605138103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Huang G, Wang H, Chou S, Nie X, Chen J, Liu H (2006) Bistable expression of WOR1, a master regulator of white-opaque switching in Candida albicans. Proc Natl Acad Sci USA 103(34):12813–12818. doi:10.1073/pnas.0605270103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Srikantha T, Borneman AR, Daniels KJ, Pujol C, Wu W, Seringhaus MR, Gerstein M, Yi S, Snyder M, Soll DR (2006) TOS9 regulates white-opaque switching in Candida albicans. Eukaryot Cell 5(10):1674–1687. doi:10.1128/EC.00252-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Guan Z, Liu H (2015) The WOR1 5′ untranslated region regulates white-opaque switching in Candida albicans by reducing translational efficiency. Mol Microbiol. doi:10.1111/mmi.13014

    PubMed Central  Google Scholar 

  110. Tuch BB, Mitrovich QM, Homann OR, Hernday AD, Monighetti CK, De La Vega FM, Johnson AD (2010) The transcriptomes of two heritable cell types illuminate the circuit governing their differentiation. PLoS Genet 6(8):e1001070. doi:10.1371/journal.pgen.1001070

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Miller MG, Johnson AD (2002) White-opaque switching in Candida albicans is controlled by mating-type locus homeodomain proteins and allows efficient mating. Cell 110(3):293–302

    Article  CAS  PubMed  Google Scholar 

  112. Bruno VM, Wang Z, Marjani SL, Euskirchen GM, Martin J, Sherlock G, Snyder M (2010) Comprehensive annotation of the transcriptome of the human fungal pathogen Candida albicans using RNA-seq. Genome Res 20(10):1451–1458. doi:10.1101/gr.109553.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lee HJ, Kim JM, Kang WK, Yang H, Kim JY (2015) The NDR kinase Cbk1 downregulates the transcriptional repressor Nrg1 through the mRNA-binding protein Ssd1 in Candida albicans. Eukaryot Cell 14(7):671–683. doi:10.1128/EC.00016-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. McNemar MD, Fonzi WA (2002) Conserved serine/threonine kinase encoded by CBK1 regulates expression of several hypha-associated transcripts and genes encoding cell wall proteins in Candida albicans. J Bacteriol 184(7):2058–2061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Uesono Y, Toh-e A, Kikuchi Y (1997) Ssd1p of Saccharomyces cerevisiae associates with RNA. J Biol Chem 272(26):16103–16109

    Article  CAS  PubMed  Google Scholar 

  116. Jansen JM, Wanless AG, Seidel CW, Weiss EL (2009) Cbk1 regulation of the RNA-binding protein Ssd1 integrates cell fate with translational control. Curr Biol 19(24):2114–2120. doi:10.1016/j.cub.2009.10.071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gank KD, Yeaman MR, Kojima S, Yount NY, Park H, Edwards JE Jr, Filler SG, Fu Y (2008) SSD1 is integral to host defense peptide resistance in Candida albicans. Eukaryot Cell 7(8):1318–1327. doi:10.1128/EC.00402-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Braun BR, van Het Hoog M, d’Enfert C, Martchenko M, Dungan J, Kuo A, Inglis DO, Uhl MA, Hogues H, Berriman M, Lorenz M, Levitin A, Oberholzer U, Bachewich C, Harcus D, Marcil A, Dignard D, Iouk T, Zito R, Frangeul L, Tekaia F, Rutherford K, Wang E, Munro CA, Bates S, Gow NA, Hoyer LL, Kohler G, Morschhauser J, Newport G, Znaidi S, Raymond M, Turcotte B, Sherlock G, Costanzo M, Ihmels J, Berman J, Sanglard D, Agabian N, Mitchell AP, Johnson AD, Whiteway M, Nantel A (2005) A human-curated annotation of the Candida albicans genome. PLoS Genet 1(1):36–57

    Article  CAS  PubMed  Google Scholar 

  119. Mitrovich QM, Tuch BB, Guthrie C, Johnson AD (2007) Computational and experimental approaches double the number of known introns in the pathogenic yeast Candida albicans. Genome Res 17(4):492–502. doi:10.1101/gr.6111907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Warenda AJ, Konopka JB (2002) Septin function in Candida albicans morphogenesis. Mol Biol Cell 13(8):2732–2746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Strijbis K, van den Burg J, Visser WF, van den Berg M, Distel B (2012) Alternative splicing directs dual localization of Candida albicans 6-phosphogluconate dehydrogenase to cytosol and peroxisomes. FEMS Yeast Res 12(1):61–68. doi:10.1111/j.1567-1364.2011.00761.x

    Article  CAS  PubMed  Google Scholar 

  122. Hwang CS, Rhie G, Kim ST, Kim YR, Huh WK, Baek YU, Kang SO (1999) Copper- and zinc-containing superoxide dismutase and its gene from Candida albicans. Biochim Biophys Acta 1427(2):245–255

    Article  CAS  PubMed  Google Scholar 

  123. Hwang CS, Rhie GE, Oh JH, Huh WK, Yim HS, Kang SO (2002) Copper- and zinc-containing superoxide dismutase (Cu/ZnSOD) is required for the protection of Candida albicans against oxidative stresses and the expression of its full virulence. Microbiology 148(Pt 11):3705–3713. doi:10.1099/00221287-148-11-3705

    Article  CAS  PubMed  Google Scholar 

  124. Rhie GE, Hwang CS, Brady MJ, Kim ST, Kim YR, Huh WK, Baek YU, Lee BH, Lee JS, Kang SO (1999) Manganese-containing superoxide dismutase and its gene from Candida albicans. Biochim Biophys Acta 1426(3):409–419

    Article  CAS  PubMed  Google Scholar 

  125. Martinez-Lopez R, Monteoliva L, Diez-Orejas R, Nombela C, Gil C (2004) The GPI-anchored protein CaEcm33p is required for cell wall integrity, morphogenesis and virulence in Candida albicans. Microbiology 150(Pt 10):3341–3354

    Article  CAS  PubMed  Google Scholar 

  126. Martinez-Lopez R, Park H, Myers CL, Gil C, Filler SG (2006) Candida albicans Ecm33p is important for normal cell wall architecture and interactions with host cells. Eukaryot Cell 5(1):140–147. doi:10.1128/EC.5.1.140-147.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gale C, Finkel D, Tao N, Meinke M, McClellan M, Olson J, Kendrick K, Hostetter M (1996) Cloning and expression of a gene encoding an integrin-like protein in Candida albicans. Proc Natl Acad Sci USA 93(1):357–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Becht P, Konig J, Feldbrugge M (2006) The RNA-binding protein Rrm4 is essential for polarity in Ustilago maydis and shuttles along microtubules. J Cell Sci 119(Pt 23):4964–4973. doi:10.1242/jcs.03287

    Article  CAS  PubMed  Google Scholar 

  129. Becht P, Vollmeister E, Feldbrugge M (2005) Role for RNA-binding proteins implicated in pathogenic development of Ustilago maydis. Eukaryot Cell 4(1):121–133. doi:10.1128/EC.4.1.121-133.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chacko N, Zhao Y, Yang E, Wang L, Cai JJ, Lin X (2015) The lncRNA RZE1 controls cryptococcal morphological transition. PLoS Genet 11(11):e1005692. doi:10.1371/journal.pgen.1005692

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Lin X, Jackson JC, Feretzaki M, Xue C, Heitman J (2010) Transcription factors Mat2 and Znf2 operate cellular circuits orchestrating opposite- and same-sex mating in Cryptococcus neoformans. PLoS Genet 6(5):e1000953. doi:10.1371/journal.pgen.1000953

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Bloom AL, Solomons JT, Havel VE, Panepinto JC (2013) Uncoupling of mRNA synthesis and degradation impairs adaptation to host temperature in Cryptococcus neoformans. Mol Microbiol 89(1):65–83. doi:10.1111/mmi.12258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Romano M, Squeglia F, Berisio R (2015) Structure and function of RNase AS: a novel virulence factor from Mycobacterium tuberculosis. Curr Med Chem 22(14):1745–1756

    Article  CAS  PubMed  Google Scholar 

  134. Moon SL, Blackinton JG, Anderson JR, Dozier MK, Dodd BJ, Keene JD, Wilusz CJ, Bradrick SS, Wilusz J (2015) XRN1 stalling in the 5′ UTR of Hepatitis C virus and Bovine Viral Diarrhea virus is associated with dysregulated host mRNA stability. PLoS Pathog 11(3):e1004708. doi:10.1371/journal.ppat.1004708

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Tan FY, Wormann ME, Loh E, Tang CM, Exley RM (2015) Characterization of a novel antisense RNA in the major pilin locus of Neisseria meningitidis influencing antigenic variation. J Bacteriol 197(10):1757–1768. doi:10.1128/JB.00082-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Johansson J, Mandin P, Renzoni A, Chiaruttini C, Springer M, Cossart P (2002) An RNA thermosensor controls expression of virulence genes in Listeria monocytogenes. Cell 110(5):551–561

    Article  PubMed  Google Scholar 

  137. Wong KK, Bouwer HG, Freitag NE (2004) Evidence implicating the 5′ untranslated region of Listeria monocytogenes actA in the regulation of bacterial actin-based motility. Cell Microbiol 6(2):155–166

    Article  CAS  PubMed  Google Scholar 

  138. Shen A, Higgins DE (2005) The 5′ untranslated region-mediated enhancement of intracellular listeriolysin O production is required for Listeria monocytogenes pathogenicity. Mol Microbiol 57(5):1460–1473. doi:10.1111/j.1365-2958.2005.04780.x

    Article  CAS  PubMed  Google Scholar 

  139. Balvay L, Soto Rifo R, Ricci EP, Decimo D, Ohlmann T (2009) Structural and functional diversity of viral IRESes. Biochim Biophys Acta 1789(9–10):542–557. doi:10.1016/j.bbagrm.2009.07.005

    Article  CAS  PubMed  Google Scholar 

  140. Gilmore SA, Voorhies M, Gebhart D, Sil A (2015) Genome-wide reprogramming of transcript architecture by temperature specifies the developmental states of the human pathogen Histoplasma. PLoS Genet 11(7):e1005395. doi:10.1371/journal.pgen.1005395

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Guida A, Lindstadt C, Maguire SL, Ding C, Higgins DG, Corton NJ, Berriman M, Butler G (2011) Using RNA-seq to determine the transcriptional landscape and the hypoxic response of the pathogenic yeast Candida parapsilosis. BMC Genom 12:628. doi:10.1186/1471-2164-12-628

    Article  CAS  Google Scholar 

  142. Freitag J, Ast J, Bolker M (2012) Cryptic peroxisomal targeting via alternative splicing and stop codon read-through in fungi. Nature 485(7399):522–525. doi:10.1038/nature11051

    Article  CAS  PubMed  Google Scholar 

  143. Grutzmann K, Szafranski K, Pohl M, Voigt K, Petzold A, Schuster S (2014) Fungal alternative splicing is associated with multicellular complexity and virulence: a genome-wide multi-species study. DNA Res 21(1):27–39. doi:10.1093/dnares/dst038

    Article  PubMed  CAS  Google Scholar 

  144. Tang S, Guo N, Patel A, Krause PR (2013) Herpes simplex virus 2 expresses a novel form of ICP34.5, a major viral neurovirulence factor, through regulated alternative splicing. J Virol 87(10):5820–5830. doi:10.1128/JVI.03500-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Pierce CG, Chaturvedi AK, Lazzell AL, Powell AT, Saville SP, McHardy SF, Lopez-Ribot JL (2015) A novel small molecule inhibitor of biofilm formation, filamentation and virulence with low potential for the development of resistance. NPJ Biofilms Microbiomes. doi:10.1038/npjbiofilms.2015.12

    PubMed  PubMed Central  Google Scholar 

  146. Fazly A, Jain C, Dehner AC, Issi L, Lilly EA, Ali A, Cao H, Fidel PL Jr, Rao RP, Kaufman PD (2013) Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis. Proc Natl Acad Sci USA 110(33):13594–13599. doi:10.1073/pnas.1305982110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Roemer T, Jiang B, Davison J, Ketela T, Veillette K, Breton A, Tandia F, Linteau A, Sillaots S, Marta C, Martel N, Veronneau S, Lemieux S, Kauffman S, Becker J, Storms R, Boone C, Bussey H (2003) Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Mol Microbiol 50(1):167–181

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thanks Brian Wickes for useful comments and suggestions. The author was supported by Grants 5R01AI083344 and 1R21AI117299 from the National Institute of Allergy and Infectious Diseases as well as a Young Investigator Award from the Max and Minnie Tomerlin Voelcker Fund. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

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  1. Department of Microbiology and Immunology, University of Texas Health Science, Center at San Antonio, 7703 Floyd Curl Drive, MC: 7758, San Antonio, TX, 78229, USA

    David Kadosh

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Kadosh, D. Control of Candida albicans morphology and pathogenicity by post-transcriptional mechanisms. Cell. Mol. Life Sci. 73, 4265–4278 (2016). https://doi.org/10.1007/s00018-016-2294-y

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