Calcineurin orchestrates hyphal growth, septation, drug resistance and pathogenesis of Aspergillus fumigatus: Where do we go from here?

Pathogens

Volumn 4, Issue 4, 2014, Pages 883-893

  Juvvadi, Praveen R ^a   Steinbach, William J ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Aspergillus fumigatus; Calcineurin; Cyclosporine A; Drug resistance; Drug target; FK506; Hyphal growth; Phosphorylation; Septation; Virulence

Indexed keywords

CALCINEURIN;

ASPERGILLUS FUMIGATUS; NONHUMAN; ORGANIZATION; PATHOGENESIS; PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; SITE DIRECTED MUTAGENESIS;

EID: 85011007241     PISSN: None     EISSN: 20760817     Source Type: Journal    
DOI: 10.3390/pathogens4040883     Document Type: Review

References (57)

1. Kontoyiannis, D. P.; Marr, K. A.; Park, B. J.; Alexander, B. D.; Anaissie, E. J.; Walsh, T. J.; Ito, J.; Andes, D. R.; Baddley, J. W.; Brown, J. M.; et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: Overview of the transplant-associated infection surveillance network (transnet) database. Clin. Infect. Dis. 2010, 50, 1091-1100.
2. Hemenway, C.; Heitman, J. Calcineurin. Cell Biochem. Biophys. 1999, 30, 115-151.
3. Ho, S.; Clipstone, N.; Timmermann, L.; Northrop, J.; Graef, I.; Fiorentino, D.; Nourse, J.; Crabtree, G. R. The mechanism of action of cyclosporin A and fk506. Clin. Immunol. Immunopathol. 1996, 80, S40-S45.
4. Breuder, T.; Hemenway, C. S.; Movva, N. R.; Cardenas, M. E.; Heitman, J. Calcineurin is essential in cyclosporin a-and fk506-sensitive yeast strains. Proc. Natl. Acad. Sci. USA 1994, 91, 5372-5376.
5. Cardenas, M. E.; Muir, R. S.; Breuder, T.; Heitman, J. Targets of immunophilin-immunosuppressant complexes are distinct highly conserved regions of calcineurin A. EMBO J. 1995, 14, 2772-2783.
6. Klee, C. B.; Crouch, T. H.; Krinks, M. H. Calcineurin: A calcium-and calmodulin-binding protein of the nervous system. Proc. Natl. Acad. Sci. USA 1979, 76, 6270-6273.
7. Rusnak, F.; Mertz, P. Calcineurin: Form and function. Physiol. Rev. 2000, 80, 1483-1521.
8. Rumi-Masante, J.; Rusinga, F. I.; Lester, T. E.; Dunlap, T. B.; Williams, T. D.; Dunker, A. K.; Weis, D. D.; Creamer, T. P. Structural basis for activation of calcineurin by calmodulin. J. Mol. Biol. 2012, 415, 307-317.
9. King, M. M.; Huang, C. Y. The calmodulin-dependent activation and deactivation of the phosphoprotein phosphatase, calcineurin, and the effect of nucleotides, pyrophosphate, and divalent metal ions. Identification of calcineurin as a Zn and Fe metalloenzyme. J. Biol. Chem. 1984, 259, 8847-8856.
10. Juvvadi, P. R.; Lamoth, F.; Steinbach, W. J. Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis. Fungal Biol. Rev. 2014, 28, 56-69.
11. Cyert, M. S.; Kunisawa, R.; Kaim, D.; Thorner, J. Yeast has homologs (CNA1 and CNA2 gene products) of mammalian calcineurin, a calmodulin-regulated phosphoprotein phosphatase. Proc. Natl. Acad. Sci. USA 1991, 88, 7376-7380.
12. Cyert, M. S. Calcineurin signaling in saccharomyces cerevisiae: How yeast go crazy in response to stress. Biochem. Biophys. Res. Commun. 2003, 311, 1143-1150.
13. Matsumoto, T. K.; Ellsmore, A. J.; Cessna, S. G.; Low, P. S.; Pardo, J. M.; Bressan, R. A.; Hasegawa, P. M. An osmotically induced cytosolic Ca2+ transient activates calcineurin signaling to mediate ion homeostasis and salt tolerance of Saccharomyces cerevisiae. J. Biol. Chem. 2002, 277, 33075-33080.
14. Mendoza, I.; Quintero, F. J.; Bressan, R. A.; Hasegawa, P. M.; Pardo, J. M. Activated calcineurin confers high tolerance to ion stress and alters the budding pattern and cell morphology of yeast cells. J. Biol. Chem. 1996, 271, 23061-23067.
15. Mendoza, I.; Rubio, F.; Rodriguez-Navarro, A.; Pardo, J. M. The protein phosphatase calcineurin is essential for nacl tolerance of Saccharomyces cerevisiae. J. Biol. Chem. 1994, 269, 8792-8796.
16. Sugiura, R.; Sio, S. O.; Shuntoh, H.; Kuno, T. Calcineurin phosphatase in signal transduction: Lessons from fission yeast. Genes Cells 2002, 7, 619-627.
17. Yoshida, T.; Toda, T.; Yanagida, M. A calcineurin-like gene ppb1+ in fission yeast: Mutant defects in cytokinesis, cell polarity, mating and spindle pole body positioning. J. Cell Sci. 1994, 107, 1725-1735.
18. Lu, Y.; Sugiura, R.; Yada, T.; Cheng, H.; Sio, S. O.; Shuntoh, H.; Kuno, T. Calcineurin is implicated in the regulation of the septation initiation network in fission yeast. Genes Cells 2002, 7, 1009-1019.
19. Kume, K.; Koyano, T.; Kanai, M.; Toda, T.; Hirata, D. Calcineurin ensures a link between the DNA replication checkpoint and microtubule-dependent polarized growth. Nat. Cell Biol. 2011, 13, 234-242.
20. Chen, Y. L.; Kozubowski, L.; Cardenas, M. E.; Heitman, J. On the roles of calcineurin in fungal growth and pathogenesis. Curr. Fungal Infect. Rep. 2010, 4, 244-255.
21. Kozubowski, L.; Heitman, J. Profiling a killer, the development of Cryptococcus neoformans. FEMS Microbiol. Rev. 2012, 36, 78-94.
22. Sanglard, D.; Ischer, F.; Marchetti, O.; Entenza, J.; Bille, J. Calcineurin a of Candida albicans: Involvement in antifungal tolerance, cell morphogenesis and virulence. Mol. Microbiol. 2003, 48, 959-976.
23. Cruz, M. C.; Fox, D. S.; Heitman, J. Calcineurin is required for hyphal elongation during mating and haploid fruiting in Cryptococcus neoformans. EMBO J. 2001, 20, 1020-1032.
24. Cruz, M. C.; Goldstein, A. L.; Blankenship, J. R.; del Poeta, M.; Davis, D.; Cardenas, M. E.; Perfect, J. R.; McCusker, J. H.; Heitman, J. Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J. 2002, 21, 546-559.
25. Kothe, G. O.; Free, S. J. Calcineurin subunit b is required for normal vegetative growth in Neurospora crassa. Fungal Genet. Biol. 1998, 23, 248-258.
26. Prokisch, H.; Yarden, O.; Dieminger, M.; Tropschug, M.; Barthelmess, I. B. Impairment of calcineurin function in Neurospora crassa reveals its essential role in hyphal growth, morphology and maintenance of the apical Ca2+ gradient. Mol. Gen. Genet. 1997, 256, 104-114.
27. Juvvadi, P. R.; Arioka, M.; Nakajima, H.; Kitamoto, K. Cloning and sequence analysis of cnaa gene encoding the catalytic subunit of calcineurin from Aspergillus oryzae. FEMS Microbiol. Lett. 2001, 204, 169-174.
28. Juvvadi, P. R.; Kuroki, Y.; Arioka, M.; Nakajima, H.; Kitamoto, K. Functional analysis of the calcineurin-encoding gene cnaa from Aspergillus oryzae: Evidence for its putative role in stress adaptation. Arch. Microbiol. 2003, 179, 416-422.
29. Nanthakumar, N. N.; Dayton, J. S.; Means, A. R. Role of Ca++/calmodulin binding proteins in Aspergillus nidulans cell cycle regulation. Prog. Cell Cycle Res. 1996, 2, 217-228.
30. Harel, A.; Bercovich, S.; Yarden, O. Calcineurin is required for sclerotial development and pathogenicity of Sclerotinia sclerotiorum in an oxalic acid-independent manner. Mol. Plant Microbe Interact. 2006, 19, 682-693.
31. Choi, J. H.; Kim, Y. S.; Lee, Y. H. Functional analysis of mcna, a gene encoding a catalytic subunit of calcineurin, in the rice blast fungus Magnaporthe oryzae. J. Microbiol. Biotechnol. 2009, 19, 11-16.
32. Schumacher, J.; de Larrinoa, I. F.; Tudzynski, B. Calcineurin-responsive zinc finger transcription factor crz1 of Botrytis cinerea is required for growth, development, and full virulence on bean plants. Eukaryot. Cell 2008, 7, 584-601.
33. Egan, J. D.; García-Pedrajas, M. D.; Andrews, D. L.; Gold, S. E. Calcineurin is an antagonist to pka protein phosphorylation required for postmating filamentation and virulence, while pp2a is required for viability in Ustilago maydis. Mol. Plant Microbe Interact. 2009, 22, 1293-1301.
34. Cervantes-Chávez, J. A.; Ali, S.; Bakkeren, G. Response to environmental stresses, cell-wall integrity, and virulence are orchestrated through the calcineurin pathway in Ustilago hordei. Mol. Plant Microbe Interact. 2010, 24, 219-232.
35. Fox, D. S.; Heitman, J. Good fungi gone bad: The corruption of calcineurin. BioEssays 2002, 24, 894-903.
36. Yu, S. J.; Chang, Y. L.; Chen, Y. L. Calcineurin signaling: Lessons from candida species. FEMS Yeast Res. 2015, doi: 10. 1093/femsyr/fov016.
37. Steinbach, W. J.; Reedy, J. L.; Cramer, R. A.; Perfect, J. R.; Heitman, J. Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections. Nat. Rev. Microbiol. 2007, 5, 418-430.
38. Lee, S. C.; Li, A.; Calo, S.; Heitman, J. Calcineurin plays key roles in the dimorphic transition and virulence of the human pathogenic zygomycete Mucor circinelloides. PLoS Pathog. 2013, 9, 289-290.
39. Lee, S. C.; Li, A.; Calo, S.; Inoue, M.; Tonthat, N. K.; Bain, J. M.; Louw, J.; Shinohara, M. L.; Erwig, L. P.; Schumacher, M. A.; et al. Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides. Mol. Microbiol. 2015, 97, 844-865.
40. Steinbach, W. J.; Cramer, R. A.; Perfect, B. Z.; Asfaw, Y. G.; Sauer, T. C.; Najvar, L. K.; Kirkpatrick, W. R.; Patterson, T. F.; Benjamin, D. K., Jr.; Heitman, J.; et al. Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus. Eukaryot. Cell 2006, 5, 1091-1103.
41. Da Silva Ferreira, M. E.; Heinekamp, T.; Härtl, A.; Brakhage, A. A.; Semighini, C. P.; Harris, S. D.; Savoldi, M.; de Gouvêa, P. F.; da Silva Goldman, M. H.; Goldman, G. H. Functional characterization of the Aspergillus fumigatus calcineurin. Fungal Genet. Biol. 2007, 44, 219-230.
42. Juvvadi, P. R.; Fortwendel, J. R.; Rogg, L. E.; Burns, K. A.; Randell, S. H.; Steinbach, W. J. Localization and activity of the calcineurin catalytic and regulatory subunit complex at the septum is essential for hyphal elongation and proper septation in Aspergillus fumigatus. Mol. Microbiol. 2011, 82, 1235-1259.
43. Juvvadi, P. R.; Fortwendel, J. R.; Pinchai, N.; Perfect, B. Z.; Heitman, J.; Steinbach, W. J. Calcineurin localizes to the hyphal septum in Aspergillus fumigatus: Implications for septum formation and conidiophore development. Eukaryot. Cell 2008, 7, 1606-1610.
44. Ichinomiya, M.; Yamada, E.; Yamashita, S.; Ohta, A.; Horiuchi, H. Class i and class ii chitin synthases are involved in septum formation in the filamentous fungus Aspergillus nidulans. Eukaryot. Cell 2005, 4, 1125-1136.
45. Fukuda, K.; Yamada, K.; Deoka, K.; Yamashita, S.; Ohta, A.; Horiuchi, H. Class iii chitin synthase chsb of aspergillus nidulans localizes at the sites of polarized cell wall synthesis and is required for conidial development. Eukaryot. Cell 2009, 8, 945-956.
46. Muszkieta, L.; Aimanianda, V.; Mellado, E.; Gribaldo, S.; Alcàzar-Fuoli, L.; Szewczyk, E.; Prevost, M. C.; Latgé, J. P. Deciphering the role of the chitin synthase families 1 and 2 in the in vivo and in vitro growth of Aspergillus fumigatus by multiple gene targeting deletion. Cell. Microbiol. 2014, 16, 1784-1805.
47. Juvvadi, P. R.; Gehrke, C.; Fortwendel, J. R.; Lamoth, F.; Soderblom, E. J.; Cook, E. C.; Hast, M. A.; Asfaw, Y. G.; Moseley, M. A.; Creamer, T. P.; et al. Phosphorylation of calcineurin at a novel serine-proline rich region orchestrates hyphal growth and virulence in Aspergillus fumigatus. PLoS Pathog. 2013, 9, doi: 10. 1371/journal. ppat. 1003564.
48. Falloon, K.; Juvvadi, P. R.; Richards, A. D.; Vargas-Muñiz, J. M.; Renshaw, H.; Steinbach, W. J. Characterization of the fkbp12-encoding genes in Aspergillus fumigatus. PLoS ONE 2015, 10, doi: 10. 1371/journal. pone. 0137869.
49. Juvvadi, P. R.; Muñoz, A.; Lamoth, F.; Soderblom, E. J.; Moseley, M. A.; Read, N. D.; Steinbach, W. J. Calcium-mediated induction of paradoxical growth following caspofungin treatment is associated with calcineurin activation and phosphorylation in Aspergillus fumigatus. Antimicrob. Agents Chemother. 2015, 59, 4946-4955.
50. Steinbach, W. J. Are we there yet? Recent progress in the molecular diagnosis and novel antifungal targeting of Aspergillus fumigatus and invasive aspergillosis. PLoS Pathog. 2013, 9, doi: 10. 1371/journal. ppat. 1003642.
51. Lamoth, F.; Juvvadi, P. R.; Steinbach, W. J. Histone deacetylase inhibition as an alternative strategy against invasive aspergillosis. Front. Microbiol. 2015, doi: 10. 3389/fmicb. 2015. 00096.
52. Lamoth, F.; Juvvadi, P. R.; Gehrke, C.; Steinbach, W. J. In vitro activity of calcineurin and heat shock protein 90 inhibitors against Aspergillus fumigatus azole-and echinocandin-resistant strains. Antimicrob. Agents Chemother. 2013, 57, 1035-1039.
53. Steinbach, W. J.; Schell, W. A.; Blankenship, J. R.; Onyewu, C.; Heitman, J.; Perfect, J. R. In vitro interactions between antifungals and immunosuppressants against Aspergillus fumigatus. Antimicrob. Agents Chemother. 2004, 48, 1664-1669.
54. Fortwendel, J. R.; Juvvadi, P. R.; Perfect, B. Z.; Rogg, L. E.; Perfect, J. R.; Steinbach, W. J. Transcriptional regulation of chitin synthases by calcineurin controls paradoxical growth of Aspergillus fumigatus in response to caspofungin. Antimicrob. Agents Chemother. 2010, 54, 1555-1563.
55. Lamoth, F.; Juvvadi, P. R.; Soderblom, E. J.; Moseley, M. A.; Steinbach, W. J. Hsp70 and the cochaperone stia (hop) orchestrate hsp90-mediated caspofungin tolerance in Aspergillus fumigatus. Antimicrob. Agents Chemother. 2015, 59, 4727-4733.
56. Lamoth, F.; Juvvadi, P. R.; Fortwendel, J. R.; Steinbach, W. J. Heat shock protein 90 is required for conidiation and cell wall integrity in Aspergillus fumigatus. Eukaryot. Cell 2012, 11, 1324-1332.
57. Lamoth, F.; Alexander, B. D.; Juvvadi, P. R.; Steinbach, W. J. Antifungal activity of compounds targeting the hsp90-calcineurin pathway against various mould species. J. Antimicrob. Chemother. 2015, 70, 1408-1411.