Mycological Progress

, Volume 16, Issue 11–12, pp 1007–1013 | Cite as

Multistep phosphorelay in fungi: the enigma of multiple signals and a limited number of signaling pathways

  • Stefan Jacob
  • Eckhard Thines


Current knowledge of fungal ecology depends on the understanding of the perception and processing of biotic and abiotic factors facilitating environmental interactions. Ongoing research regarding fungal signaling mechanisms has not only increased our appreciation for multistep phosphorelay signaling systems as an asset, but also sheds light on the role that these upgrades of the simple two-component signaling systems play in fungal biology, stress response, differentiation processes, metabolism, and pathogenicity. In contrast to two-component signaling systems, multistep phosphorelay systems comprise a phosphotransfer protein enabling modular phosphate transfer from the sensor hybrid histidine kinase to the response regulator protein. Histidine kinases were found to perceive a lot of environmental signals and integrate them into a number of signaling pathways. The major question is how multistep phosphorelay signal transduction takes place in detail, since most fungi possess only one single histidine-containing phosphotransfer protein enabling phosphate transfer. One single phosphotransfer protein routes various signals in a specific way and coordinates the phosphates precisely to different target locations within the cell. This mini review opens the door and presents three hypotheses as the basis for further investigations to unravel the complex signaling mechanisms in fungal multistep phosphorelay systems. Scaffold proteins, frequency-based signaling, and alternative splicing are discussed as putative candidates to implement fungal signaling in multistep phosphorelay systems having only one phosphotransfer protein for coordinated phosphate transfer.


Multistep phosphorelay Alternative splicing Phosphotransfer protein Ypd1 Scaffold, histidine kinase 


  1. Albeck JG, Mills GB, Brugge JS (2013) Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals. Mol Cell 49(2):249–261CrossRefPubMedGoogle Scholar
  2. Allen GJ, Chu SP, Harrington CL, Schumacher K, Hoffmann T, Tang YY, Grill E, Schroeder JI (2001) A defined range of guard cell calcium oscillation parameters encodes stomatal movements. Nature 411(6841):1053–1057CrossRefPubMedGoogle Scholar
  3. Banno S, Noguchi R, Yamashita K, Fukumori F, Kimura M, Yamaguchi I, Fujimura M (2007) Roles of putative His-to-Asp signaling modules HPT-1 and RRG-2, on viability and sensitivity to osmotic and oxidative stresses in Neurospora crassa. Curr Genet 51(3):197–208CrossRefPubMedGoogle Scholar
  4. Boyce KJ, Schreider L, Kirszenblat L, Andrianopoulos A (2011) The two-component histidine kinases DrkA and SlnA are required for in vivo growth in the human pathogen Penicillium marneffei. Mol Microbiol 82(5):1164–1184CrossRefPubMedGoogle Scholar
  5. Brewster JL, de Valoir T, Dwyer ND, Winter E, Gustin MC (1993) An osmosensing signal transduction pathway in yeast. Science 260(5102):1760–1762CrossRefGoogle Scholar
  6. Catlett NL, Yoder OC, Turgeon BG (2003) Whole-genome analysis of two-component signal transduction genes in fungal pathogens. Eukaryot Cell 2(6):1151–1161CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chen RE, Thorner J (2007) Function and regulation in MAPK signaling pathways: lessons learned from the yeast Saccharomyces cerevisiae. Biochim Biophys Acta 1773(8):1311–1340CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chol K-Y, Satterberg B, Lyons DM, Elion EA (1994) Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Cell 78(3):499–512CrossRefGoogle Scholar
  9. Connolly LR, Smith KM, Freitag M (2013) The Fusarium graminearum histone H3 K27 methyltransferase KMT6 regulates development and expression of secondary metabolite gene clusters. PLoS Genet 9(10):e1003916CrossRefPubMedPubMedCentralGoogle Scholar
  10. Defosse TA, Sharma A, Mondal AK, Dugé de Bernonville T, Latgé J-P, Calderone R, Giglioli‐Guivarc’h N, Courdavault V, Clastre M, Papon N (2015) Hybrid histidine kinases in pathogenic fungi. Mol Microbiol 95(6):914–924CrossRefPubMedGoogle Scholar
  11. Dettmann A, Illgen J, März S, Schürg T, Fleissner A, Seiler S (2012) The NDR kinase scaffold HYM1/MO25 is essential for MAK2 MAP kinase signaling in Neurospora crassa. PLoS Genet 8(9):e1002950CrossRefPubMedPubMedCentralGoogle Scholar
  12. Duan Y, Ge C, Liu S, Wang J, Zhou M (2013) A two-component histidine kinase Shk1 controls stress response, sclerotial formation and fungicide resistance in Sclerotinia sclerotiorum. Mol Plant Pathol 14(7):708–718CrossRefPubMedGoogle Scholar
  13. Engelberg D, Perlman R, Levitzki A (2014) Transmembrane signaling in Saccharomyces cerevisiae as a model for signaling in metazoans: state of the art after 25years. Cell Signal 26(12):2865–2878CrossRefPubMedGoogle Scholar
  14. Fassler JS, West AH (2013) Histidine phosphotransfer proteins in fungal two-component signal transduction pathways. Eukaryot Cell 12(8):1052–1060CrossRefPubMedPubMedCentralGoogle Scholar
  15. Grebe TW, Stock JB (1999) The histidine protein kinase superfamily. Adv Microb Physiol 41:139–227CrossRefPubMedGoogle Scholar
  16. Grützmann 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 21:27–39CrossRefPubMedGoogle Scholar
  17. Hagiwara D, Takahashi-Nakaguchi A, Toyotome T, Yoshimi A, Abe K, Kamei K, Gonoi T, Kawamoto S (2013) NikA/TcsC histidine kinase is involved in conidiation, hyphal morphology, and responses to osmotic stress and antifungal chemicals in Aspergillus fumigatus. PLoS One 8(12):e80881CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hayashi M, Maeda T (2006) Activation of the HOG pathway upon cold stress in Saccharomyces cerevisiae. J Biochem 139(4):797–803CrossRefPubMedGoogle Scholar
  19. Hérivaux A, So Y-S, Gastebois A, Latgé J-P, Bouchara J-P, Bahn Y-S, Papon N (2016) Major sensing proteins in pathogenic fungi: the hybrid histidine kinase family. PLoS Pathog 12(7):e1005683CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hilioti Z, Sabbagh W, Paliwal S, Bergmann A, Goncalves MD, Bardwell L, Levchenko A (2008) Oscillatory phosphorylation of yeast Fus3 MAP kinase controls periodic gene expression and morphogenesis. Curr Biol 18:1700–1706CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hirata H, Yoshiura S, Ohtsuka T, Bessho Y, Harada T, Yoshikawa K, Kageyama R (2002) Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science 298(5594):840–843CrossRefPubMedGoogle Scholar
  22. Hohmann S (2009) Control of high osmolarity signalling in the yeast Saccharomyces cerevisiae. FEBS Lett 583(24):4025–4029CrossRefPubMedGoogle Scholar
  23. Jacob S (2016) Phosphotransfer protein Ypd1p is essential for fludioxonil action in phytopathogenic fungi. Fungal Genomics Biol 6:140CrossRefGoogle Scholar
  24. Jacob S, Yemelin A (2016) Stress biology in fungi and “Omic” approaches as suitable tools for analyzing plant–microbe interactions. In: Host–pathogen interaction. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 153–178Google Scholar
  25. Jacob S, Foster AJ, Yemelin A, Thines E (2014) Histidine kinases mediate differentiation, stress response, and pathogenicity in Magnaporthe oryzae. Microbiol Open 3(5):668–687CrossRefGoogle Scholar
  26. Jacob S, Foster AJ, Yemelin A, Thines E (2015) High osmolarity glycerol (HOG) signalling in Magnaporthe oryzae: identification of MoYPD1 and its role in osmoregulation, fungicide action, and pathogenicity. Fungal Biol 119(7):580–594CrossRefPubMedGoogle Scholar
  27. Jacob S, Schüffler A, Thines E (2016) Hog1p activation by marasmic acid through inhibition of the histidine kinase Sln1p. Pest Manag Sci 72(6):1268–1274CrossRefPubMedPubMedCentralGoogle Scholar
  28. Jacob S, Yemelin A, Bohnert S, Andresen K, Thines E (2017) The exceptionality of stress response in Magnaporthe oryzae: a set of “salt stress-induced” genes unique to the rice blast fungus. J Plant Dis Protect 124(4):399–402CrossRefGoogle Scholar
  29. Jin L, Li G, Yu D, Huang W, Cheng C, Liao S, Wu Q, Zhang Y (2017) Transcriptome analysis reveals the complexity of alternative splicing regulation in the fungus Verticillium dahliae. BMC Genomics 18(1):130CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kennedy EN, Menon SK, West AH (2016) Extended N-terminal region of the essential phosphorelay signaling protein Ypd1 from Cryptococcus neoformans contributes to structural stability, phosphostability and binding of calcium ions. FEMS Yeast Res 16(6):fow068CrossRefPubMedGoogle Scholar
  31. Konte T, Terpitz U, Plemenitaš A (2016) Reconstruction of the high-osmolarity glycerol (HOG) signaling pathway from the halophilic fungus Wallemia ichthyophaga in Saccharomyces cerevisiae. Front Microbiol 7:901CrossRefPubMedPubMedCentralGoogle Scholar
  32. Lawrence CL, Botting CH, Antrobus R, Coote PJ (2004) Evidence of a new role for the high-osmolarity glycerol mitogen-activated protein kinase pathway in yeast: regulating adaptation to citric acid stress. Mol Cell Biol 24(8):3307–3323CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lee Y, Rio DC (2015) Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem 84(1):291–323CrossRefPubMedPubMedCentralGoogle Scholar
  34. Lee J-W, Ko Y-J, Kim S-Y, Bahn Y-S (2011) Multiple roles of Ypd1 phosphotransfer protein in viability, stress response, and virulence factor regulation in Cryptococcus neoformans. Eukaryot Cell 10(7):998–1002CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lev Maor G, Yearim A, Ast G (2015) The alternative role of DNA methylation in splicing regulation. Trends Genet 31(5):274–280CrossRefPubMedGoogle Scholar
  36. Liang X-L, Liu J-L, Liu S-S, Liang X-N, Zhang S-H (2015) Alternatively spliced SMN orthologue in Magnaporthe oryzae is required for stress resistance and disease development. Eur J Plant Pathol 142(3):427–439CrossRefGoogle Scholar
  37. Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T (2010) Regulation of alternative splicing by histone modifications. Science 327(5968):996–1000CrossRefPubMedPubMedCentralGoogle Scholar
  38. Maeda T, Wurgler-Murphy SM, Saito H (1994) A two-component system that regulates an osmosensing MAP kinase cascade in yeast. Nature 369(6477):242–245CrossRefPubMedGoogle Scholar
  39. Marshall AN, Montealegre MC, Jiménez-López C, Lorenz MC, van Hoof A (2013) Alternative splicing and subfunctionalization generates functional diversity in fungal proteomes. PLoS Genet 9(3):e1003376CrossRefPubMedPubMedCentralGoogle Scholar
  40. Mavrianos J, Desai C, Chauhan N (2014) Two-component histidine phosphotransfer protein Ypd1 is not essential for viability in Candida albicans. Eukaryot Cell 13(4):452–460CrossRefPubMedPubMedCentralGoogle Scholar
  41. McCormick A, Jacobsen ID, Broniszewska M, Beck J, Heesemann J, Ebel F (2012) The two-component sensor Kinase TcsC and its role in stress resistance of the human-pathogenic mold Aspergillus fumigatus. PLoS One 7(6):e38262CrossRefPubMedPubMedCentralGoogle Scholar
  42. Mitra RM, Gleason CA, Edwards A, Hadfield J, Downie JA, Oldroyd GED, Long SR (2004) A Ca2+/calmodulin-dependent protein kinase required for symbiotic nodule development: gene identification by transcript-based cloning. Proc Natl Acad Sci U S A 101(13):4701–4705CrossRefPubMedPubMedCentralGoogle Scholar
  43. Naftelberg S, Schor IE, Ast G, Kornblihtt AR (2015) Regulation of alternative splicing through coupling with transcription and chromatin structure. Annu Rev Biochem 84(1):165–198CrossRefPubMedGoogle Scholar
  44. Nagahashi S, Mio T, Ono N, Yamada-Okabe T, Arisawa M, Bussey H, Yamada-Okabe H (1998) Isolation of CaSLN1 and CaNIK1, the genes for osmosensing histidine kinase homologues, from the pathogenic fungus Candida albicans. Microbiology 144(2):425–432CrossRefPubMedGoogle Scholar
  45. Niwa Y, Masamizu Y, Liu T, Nakayama R, Deng C-X, Kageyama R (2007) The initiation and propagation of Hes7 oscillation are cooperatively regulated by Fgf and notch signaling in the somite segmentation clock. Dev Cell 13(2):298–304CrossRefPubMedGoogle Scholar
  46. Oates AC, Morelli LG, Ares S (2012) Patterning embryos with oscillations: structure, function and dynamics of the vertebrate segmentation clock. Development 139(4):625–639CrossRefPubMedGoogle Scholar
  47. Pham KTM, Inoue Y, Vu BV, Nguyen HH, Nakayashiki T, Ikeda K, Nakayashiki H (2015) MoSET1 (histone H3K4 methyltransferase in Magnaporthe oryzae) regulates global gene expression during infection-related morphogenesis. PLoS Genet 11(7):e1005385CrossRefPubMedPubMedCentralGoogle Scholar
  48. Posas F, Wurgler-Murphy SM, Maeda T, Witten EA, Thai TC, Saito H (1996) Yeast HOG1 MAP kinase cascade is regulated by a multistep phosphorelay mechanism in the SLN1–YPD1–SSK1 “two-component” osmosensor. Cell 86(6):865–875CrossRefPubMedGoogle Scholar
  49. Posas F, Witten EA, Saito H (1998) Requirement of STE50 for osmostress-induced activation of the STE11 mitogen-activated protein kinase kinase kinase in the high-osmolarity glycerol response pathway. Mol Cell Biol 18(10):5788–5796CrossRefPubMedPubMedCentralGoogle Scholar
  50. Printen JA, Sprague GF (1994) Protein–protein interactions in the yeast pheromone response pathway: Ste5p interacts with all members of the MAP kinase cascade. Genetics 138(3):609–619PubMedPubMedCentralGoogle Scholar
  51. Rispail N, Di Pietro A (2010) The two-component histidine kinase Fhk1 controls stress adaptation and virulence of Fusarium oxysporum. Mol Plant Pathol 11(3):395–407CrossRefPubMedGoogle Scholar
  52. Saito H (2010) Regulation of cross-talk in yeast MAPK signaling pathways. Curr Opin Microbiol 13(6):677–683CrossRefPubMedGoogle Scholar
  53. Sarrazin AF, Peel AD, Averof M (2012) A segmentation clock with two-segment periodicity in insects. Science 336(6079):338–341CrossRefPubMedGoogle Scholar
  54. Smith DA, Morgan BA, Quinn J (2010) Stress signalling to fungal stress-activated protein kinase pathways. FEMS Microbiol Lett 306(1):1–8CrossRefPubMedPubMedCentralGoogle Scholar
  55. Sonnen KF, Aulehla A (2014) Dynamic signal encoding—from cells to organisms. Semin Cell Dev Biol 34:91–98CrossRefPubMedGoogle Scholar
  56. Stock AM, Robinson VL, Goudreau PN (2000) Two-component signal transduction. Annu Rev Biochem 69(1):183–215CrossRefPubMedGoogle Scholar
  57. Studt L, Schmidt FJ, Jahn L, Sieber CMK, Connolly LR, Niehaus E-M, Freitag M, Humpf HU, Tudzynski B (2013) Two histone deacetylases, FfHda1 and FfHda2, are important for Fusarium fujikuroi secondary metabolism and virulence. Appl Environ Microbiol 79(24):7719–7734CrossRefPubMedPubMedCentralGoogle Scholar
  58. Su J, Xu J, Zhang S (2015) RACK1, scaffolding a heterotrimeric G protein and a MAPK cascade. Trends Plant Sci 20(7):405–407CrossRefPubMedGoogle Scholar
  59. Thorsen M, Di Y, Tängemo C, Morillas M, Ahmadpour D, Van der Does C, Wagner A, Johansson E, Boman J, Posas F, Wysocki R, Tamás MJ (2006) The MAPK Hog1p modulates Fps1p-dependent arsenite uptake and tolerance in yeast. Mol Biol Cell 17(10):4400–4410CrossRefPubMedPubMedCentralGoogle Scholar
  60. Tilgner H, Nikolaou C, Althammer S, Sammeth M, Beato M, Valcárcel J, Guigó R (2009) Nucleosome positioning as a determinant of exon recognition. Nat Struct Mol Biol 16(9):996–1001CrossRefPubMedGoogle Scholar
  61. Utzny C, Faroudi M, Valitutti S (2005) Frequency encoding of T-cell receptor engagement dynamics in calcium time series. Biophys J 88(1):1–14CrossRefPubMedGoogle Scholar
  62. Vargas-Pérez I, Sánchez O, Kawasaki L, Georgellis D, Aguirre J (2007) Response regulators SrrA and SskA are central components of a phosphorelay system involved in stress signal transduction and asexual sporulation in Aspergillus nidulans. Eukaryot Cell 6(9):1570–1583CrossRefPubMedPubMedCentralGoogle Scholar
  63. Viaud M, Fillinger S, Liu W, Polepalli JS, Le Pêcheur P, Kunduru AR, Leroux P, Legendre L (2006) A class III histidine kinase acts as a novel virulence factor in Botrytis cinerea. Mol Plant Microbe Interact 19(9):1042–1050CrossRefPubMedGoogle Scholar
  64. Wolanin PM, Thomason PA, Stock JB (2002) Histidine protein kinases: key signal transducers outside the animal kingdom. Genome Biol 3(10):reviews3013.1CrossRefGoogle Scholar
  65. Xie B-B, Li D, Shi W-L, Qin Q-L, Wang X-W, Rong J-C, Sun C-Y, Huang F, Zhang X-Y, Dong X-W, Chen X-L, Zhou B-C, Zhang Y-Z, Song X-Y (2015) Deep RNA sequencing reveals a high frequency of alternative splicing events in the fungus Trichoderma longibrachiatum. BMC Genomics 16(1):54CrossRefPubMedPubMedCentralGoogle Scholar
  66. Yamada-Okabe T, Mio T, Ono N, Kashima Y, Matsui M, Arisawa M, Yamada-Okabe H (1999) Roles of three histidine kinase genes in hyphal development and virulence of the pathogenic fungus Candida albicans. J Bacteriol 181(23):7243–7247PubMedPubMedCentralGoogle Scholar

Copyright information

© German Mycological Society and Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Institut für Biotechnologie und Wirkstoff-Forschung gGmbH (IBWF)KaiserslauternGermany
  2. 2.Johannes Gutenberg-University Mainz, Mikrobiologie und Weinforschung am Institut für Molekulare PhysiologieMainzGermany

Personalised recommendations