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Cited by 25Fungal Infections and StudiesFungal and yeast genetics researchProtein Kinase Regulation and GTPase Signaling

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The Cryptococcus neoformans STRIPAK complex controls genome stability, sexual development, and virulence

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Peterson, Patricia P., Choi, Jin-Tae, Fu, Ci, Cowen, Leah E., Sun, Sheng, Bahn, Yong-Sun, Heitman, Joseph·2024·PLOS Pathogens
DOI 10.1371/journal.ppat.1012735PMC PMC11614259

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Abstract

The eukaryotic serine/threonine protein phosphatase PP2A is a heterotrimeric enzyme composed of a scaffold A subunit, a regulatory B subunit, and a catalytic C subunit. Of the four known B subunits, the B”’ subunit (known as striatin) interacts with the multi-protein striatin-interacting phosphatase and kinase (STRIPAK) complex. Orthologs of STRIPAK components were identified in Cryptococcus neoformans , namely PP2AA/Tpd3, PP2AC/Pph22, PP2AB/Far8, STRIP/Far11, SLMAP/Far9, and Mob3. Structural modeling, protein domain analysis, and detected protein-protein interactions suggest C . neoformans STRIPAK is assembled similarly to the human and fungal orthologs. Here, STRIPAK components Pph22, Far8, and Mob3 were functionally characterized. Whole-genome sequencing revealed that mutations in STRIPAK complex subunits lead to increased segmental and chromosomal aneuploidy, suggesting STRIPAK functions in maintaining genome stability. We demonstrate that PPH22 is a haploinsufficient gene: heterozygous PPH22/pph22 Δ mutant diploid strains exhibit defects in hyphal growth and sporulation and have a significant fitness disadvantage when grown in competition against a wild-type diploid. Deletion mutants pph22 Δ, far8 Δ, and mob3 Δ exhibit defects in mating and sexual differentiation, including impaired hyphae, basidia, and basidiospore production. Loss of either PPH22 or FAR8 in a haploid background leads to growth defects at 30°C, severely reduced growth at elevated temperature, abnormal cell morphology, and impaired virulence. Additionally, pph22 Δ strains frequently accumulate suppressor mutations that result in overexpression of another putative PP2A catalytic subunit, PPG1 . The pph22 Δ and far8 Δ mutants are also unable to grow in the presence of the calcineurin inhibitors cyclosporine A or FK506, and thus these mutations are synthetically lethal with loss of calcineurin activity. Conversely, mob3 Δ mutants display increased thermotolerance, capsule production, and melanization, and are hypervirulent in a murine infection model. Taken together, these findings reveal that the C . neoformans STRIPAK complex plays an important role in genome stability, vegetative growth, sexual development, and virulence in this prominent human fungal pathogen.

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References 87 · Cited by 25

Research works printed but not linked: 81

  1. V Janssens, 2001, Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling, Biochem J, 353, 417, 10.1042/bj3530417 · DOI
  2. J Gordon, 2011, Protein phosphatase 2a (PP2A) binds within the oligomerization domain of striatin and regulates the phosphorylation and activation of the mammalian Ste20-Like kinase Mst3., BMC biochemistry, 12, 54, 10.1186/1471-2091-12-54 · DOI
  3. Goudreault M, 2009, A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein., Mol Cell Proteomics, 8, 157, 10.1074/mcp.M800266-MCP200 · DOI · Paper page
  4. MJ Kean, 2011, Structure-Function Analysis of Core STRIPAK Proteins: A Signaling Complex Implicated In Golgi Polarization, J Biol Chem, 286, 25065, 10.1074/jbc.M110.214486 · DOI
  5. PS Ribeiro, 2010, Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling, Mol Cell, 39, 521, 10.1016/j.molcel.2010.08.002 · DOI
  6. Y Bernhards, 2011, The phocein homologue SmMOB3 is essential for vegetative cell fusion and sexual development in the filamentous ascomycete Sordaria macrospora, Curr Genet, 57, 133, 10.1007/s00294-010-0333-z · DOI
  7. N Elramli, 2019, Assembly of a heptameric STRIPAK complex is required for coordination of light-dependent multicellular fungal development with secondary metabolism in Aspergillus nidulans, PLoS Genet, 15, e1008053, 10.1371/journal.pgen.1008053 · DOI
  8. A Dettmann, 2013, HAM-2 and HAM-3 are central for the assembly of the Neurospora STRIPAK complex at the nuclear envelope and regulate nuclear accumulation of the MAP kinase MAK-1 in a MAK-2-dependent manner, Mol Microbiol, 90, 796, 10.1111/mmi.12399 · DOI
  9. S Bloemendal, 2012, A homologue of the human STRIPAK complex controls sexual development in fungi, Mol Microbiol, 84, 310, 10.1111/j.1365-2958.2012.08024.x · DOI
  10. D Radchenko, 2018, A Hippo Pathway-Related GCK Controls Both Sexual and Vegetative Developmental Processes in the Fungus Sordaria macrospora, Genetics, 210, 137, 10.1534/genetics.118.301261 · DOI
  11. A Beier, 2016, Catalytic Subunit 1 of Protein Phosphatase 2A Is a Subunit of the STRIPAK Complex and Governs Fungal Sexual Development., mBio, 7, 10.1128/mBio.00870-16 · DOI
  12. H Zhang, 2018, Fsr1, a striatin homologue, forms an endomembrane-associated complex that regulates virulence in the maize pathogen Fusarium verticillioides, Mol Plant Pathol, 19, 812, 10.1111/mpp.12562 · DOI
  13. KT Islam, 2017, FvSTR1, a striatin orthologue in Fusarium virguliforme, is required for asexual development and virulence, Appl Microbiol Biotechnol, 101, 6431, 10.1007/s00253-017-8387-1 · DOI
  14. T Pracheil, 2013, Tiered assembly of the yeast Far3-7-8-9-10-11 complex at the endoplasmic reticulum, J Biol Chem, 288, 16986, 10.1074/jbc.M113.451674 · DOI
  15. S Nordzieke, 2015, A fungal sarcolemmal membrane-associated protein (SLMAP) homolog plays a fundamental role in development and localizes to the nuclear envelope, endoplasmic reticulum, and mitochondria., Eukaryot Cell, 14, 345, 10.1128/EC.00241-14 · DOI
  16. EJ Reschka, 2018, A novel STRIPAK complex component mediates hyphal fusion and fruiting-body development in filamentous fungi, Mol Microbiol, 110, 513, 10.1111/mmi.14106 · DOI
  17. S Frey, 2015, Germinal Center Kinases SmKIN3 and SmKIN24 Are Associated with the Sordaria macrospora Striatin-Interacting Phosphatase and Kinase (STRIPAK) Complex., PLoS One., 10, e0139163, 10.1371/journal.pone.0139163 · DOI
  18. CL Wang, 2010, Aspergillus nidulans striatin (StrA) mediates sexual development and localizes to the endoplasmic reticulum., Fungal Genet Biol, 47, 789, 10.1016/j.fgb.2010.06.007 · DOI
  19. KA Green, 2016, An Epichloe festucae homologue of MOB3, a component of the STRIPAK complex, is required for the establishment of a mutualistic symbiotic interaction with Lolium perenne, Mol Plant Pathol, 17, 1480, 10.1111/mpp.12443 · DOI
  20. V Gautier, 2018, PaPro1 and IDC4, Two Genes Controlling Stationary Phase, Sexual Development and Cell Degeneration in Podospora anserina., J Fungi (Basel), 4
  21. CL Wang, 2016, The Colletotrichum graminicola striatin orthologue Str1 is necessary for anastomosis and is a virulence factor, Mol Plant Pathol, 17, 931, 10.1111/mpp.12339 · DOI
  22. A Frost, 2012, Functional repurposing revealed by comparing S. pombe and S. cerevisiae genetic interactions, Cell, 149, 1339, 10.1016/j.cell.2012.04.028 · DOI
  23. A Chen, 2023, The STRIPAK complex orchestrates cell wall integrity signalling to govern the fungal development and virulence of Fusarium graminearum, Mol Plant Pathol, 24, 1139, 10.1111/mpp.13359 · DOI
  24. S Poggeler, 2004, A WD40 repeat protein regulates fungal cell differentiation and can be replaced functionally by the mammalian homologue striatin, Eukaryot Cell, 3, 232, 10.1128/EC.3.1.232-240.2004 · DOI
  25. AL Couzens, 2013, Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions., Sci Signal., 6, rs15, 10.1126/scisignal.2004712 · DOI
  26. SJ Bae, 2017, SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK., Elife, 6
  27. U Kuck, 2021, STRIPAK, a Key Regulator of Fungal Development, Operates as a Multifunctional Signaling Hub., J Fungi (Basel)., 7, 443, 10.3390/jof7060443 · DOI
  28. U Kuck, 2019, STRIPAK, a highly conserved signaling complex, controls multiple eukaryotic cellular and developmental processes and is linked with human diseases, Biol Chem
  29. T Pracheil, 2012, TORC2 signaling is antagonized by protein phosphatase 2A and the Far complex in Saccharomyces cerevisiae, Genetics, 190, 1325, 10.1534/genetics.111.138305 · DOI
  30. HA Kemp, 2003, Far3 and five interacting proteins prevent premature recovery from pheromone arrest in the budding yeast Saccharomyces cerevisiae, Mol Cell Biol, 23, 1750, 10.1128/MCB.23.5.1750-1763.2003 · DOI
  31. A Innokentev, 2020, Association and dissociation between the mitochondrial Far complex and Atg32 regulate mitophagy., Elife., 9, 10.7554/eLife.63694 · DOI
  32. K Furukawa, 2021, Mitophagy regulation mediated by the Far complex in yeast, Autophagy, 17, 1042, 10.1080/15548627.2021.1885184 · DOI
  33. Y Yamamura, 2008, The coiled-coil protein-binding motif in Fusarium verticillioides Fsr1 is essential for maize stalk rot virulence, Microbiology (Reading)., 154, 1637, 10.1099/mic.0.2008/016782-0 · DOI
  34. Y Du, 2013, A serine/threonine-protein phosphatase PP2A catalytic subunit is essential for asexual development and plant infection in Magnaporthe oryzae, Curr Genet, 59, 33, 10.1007/s00294-012-0385-3 · DOI
  35. R Rajasingham, 2022, The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis, Lancet Infect Dis, 22, 1748, 10.1016/S1473-3099(22)00499-6 · DOI
  36. Y Zhao, 2019, Life Cycle of Cryptococcus neoformans, Annu Rev Microbiol, 73, 17, 10.1146/annurev-micro-020518-120210 · DOI
  37. A Casadevall, 2019, The capsule of Cryptococcus neoformans., Virulence, 10, 822, 10.1080/21505594.2018.1431087 · DOI
  38. MA Garcia-Solache, 2010, Global warming will bring new fungal diseases for mammals., mBio, 1
  39. D Lee, 2019, Unraveling Melanin Biosynthesis and Signaling Networks in Cryptococcus neoformans., mBio, 10
  40. JH Jin, 2020, Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans, Nature communications, 11, 4212, 10.1038/s41467-020-18028-0 · DOI
  41. C Chen, 2014, Striatins contain a noncanonical coiled coil that binds protein phosphatase 2A A subunit to form a 2:2 heterotetrameric core of striatin-interacting phosphatase and kinase (STRIPAK) complex., J Biol Chem, 289, 9651, 10.1074/jbc.M113.529297 · DOI · Paper page
  42. BC Jeong, 2021, Cryo-EM structure of the Hippo signaling integrator human STRIPAK, Nature structural & molecular biology, 28, 290, 10.1038/s41594-021-00564-y · DOI
  43. JT Byers, 2009, Hydrophobic profiles of the tail anchors in SLMAP dictate subcellular targeting, BMC cell biology, 10, 48, 10.1186/1471-2121-10-48 · DOI
  44. TD Goddard, 2018, UCSF ChimeraX: Meeting modern challenges in visualization and analysis, Protein Sci, 27, 14, 10.1002/pro.3235 · DOI · Paper page
  45. W van Zyl, 1992, Inactivation of the protein phosphatase 2A regulatory subunit A results in morphological and transcriptional defects in Saccharomyces cerevisiae, Mol Cell Biol, 12, 4946
  46. AA Sneddon, 1990, Saccharomyces cerevisiae protein phosphatase 2A performs an essential cellular function and is encoded by two genes, Embo J, 9, 4339, 10.1002/j.1460-2075.1990.tb07883.x · DOI
  47. G Hu, 2011, Variation in chromosome copy number influences the virulence of Cryptococcus neoformans and occurs in isolates from AIDS patients, BMC Genomics, 12, 526, 10.1186/1471-2164-12-526 · DOI
  48. KJ Gerik, 2005, Cell wall integrity is dependent on the PKC1 signal transduction pathway in Cryptococcus neoformans, Mol Microbiol, 58, 393, 10.1111/j.1365-2958.2005.04843.x · DOI
  49. K Furukawa, 2018, The PP2A-like Protein Phosphatase Ppg1 and the Far Complex Cooperatively Counteract CK2-Mediated Phosphorylation of Atg32 to, Inhibit Mitophagy. Cell reports, 23, 3579, 10.1016/j.celrep.2018.05.064 · DOI
  50. S Niphadkar, 2024, The PP2A-like phosphatase Ppg1 mediates assembly of the Far complex to balance gluconeogenic outputs and enables adaptation to glucose depletion., PLoS Genet., 20, e1011202, 10.1371/journal.pgen.1011202 · DOI
  51. DL Toffaletti, 1993, Gene transfer in Cryptococcus neoformans by use of biolistic delivery of DNA, J Bacteriol, 175, 1405, 10.1128/jb.175.5.1405-1411.1993 · DOI
  52. FJ Walton, 2005, Novel gene functions required for melanization of the human pathogen Cryptococcus neoformans, Mol Microbiol, 57, 1381, 10.1111/j.1365-2958.2005.04779.x · DOI
  53. H Kim, 2015, Network-assisted genetic dissection of pathogenicity and drug resistance in the opportunistic human pathogenic fungus Cryptococcus neoformans., Sci Rep, 5, 8767, 10.1038/srep08767 · DOI
  54. U Kuck, 2016, The composition and function of the striatin-interacting phosphatases and kinases (STRIPAK) complex in fungi., Fungal Genet Biol, 90, 31, 10.1016/j.fgb.2015.10.001 · DOI
  55. J Hwang, 2014, STRIPAK complexes: structure, biological function, and involvement in human diseases, Int J Biochem Cell Biol, 47, 118, 10.1016/j.biocel.2013.11.021 · DOI
  56. C Fu, 2011, Identification and characterization of genes required for cell-to-cell fusion in Neurospora crassa, Eukaryot Cell, 10, 1100, 10.1128/EC.05003-11 · DOI
  57. S. Hohmann, 2002, Osmotic stress signaling and osmoadaptation in yeasts, Microbiol Mol Biol Rev, 66, 300, 10.1128/MMBR.66.2.300-372.2002 · DOI
  58. YS Bahn, 2013, Stress signaling pathways for the pathogenicity of Cryptococcus, Eukaryot Cell, 12, 1564, 10.1128/EC.00218-13 · DOI · Paper page
  59. A Odom, 1997, Calcineurin is required for virulence of Cryptococcus neoformans, EMBO J, 16, 2576, 10.1093/emboj/16.10.2576 · DOI · Paper page
  60. CS Hemenway, 1999, Calcineurin. Structure, function, and inhibition, Cell Biochem Biophys, 30, 115
  61. V Yadav, 2023, Calcineurin: The Achilles’ heel of fungal pathogens., PLoS Pathog., 19, e1011445, 10.1371/journal.ppat.1011445 · DOI
  62. RA Sia, 2000, Diploid strains of the pathogenic basidiomycete Cryptococcus neoformans are thermally dimorphic, Fungal Genet Biol, 29, 153, 10.1006/fgbi.2000.1192 · DOI
  63. RC Davidson, 2002, A PCR-based strategy to generate integrative targeting alleles with large regions of homology, Microbiology (Reading)., 148, 2607, 10.1099/00221287-148-8-2607 · DOI
  64. CM Hull, 2002, Cell identity and sexual development in Cryptococcus neoformans are controlled by the mating-type-specific homeodomain protein Sxi1alpha, Genes Dev, 16, 3046, 10.1101/gad.1041402 · DOI · Paper page
  65. A. Idnurm, 2010, A tetrad analysis of the basidiomycete fungus Cryptococcus neoformans, Genetics, 185, 153, 10.1534/genetics.109.113027 · DOI
  66. JR Perfect, 1993, The gene encoding phosphoribosylaminoimidazole carboxylase (ADE2) is essential for growth of Cryptococcus neoformans in cerebrospinal fluid, Infect Immun, 61, 4446, 10.1128/iai.61.10.4446-4451.1993 · DOI
  67. S Sudarshan, 1999, Molecular analysis of the Cryptococcus neoformans ADE2 gene, a selectable marker for transformation and gene disruption, Fungal Genet Biol, 27, 36, 10.1006/fgbi.1999.1126 · DOI
  68. X Lin, 2015, Generation of stable mutants and targeted gene deletion strains in Cryptococcus neoformans through electroporation, Med Mycol, 53, 225, 10.1093/mmy/myu083 · DOI
  69. RC Davidson, 2000, Gene disruption by biolistic transformation in serotype D strains of Cryptococcus neoformans, Fungal Genet Biol, 29, 38, 10.1006/fgbi.1999.1180 · DOI
  70. MY Huang, 2022, Short homology-directed repair using optimized Cas9 in the pathogen Cryptococcus neoformans enables rapid gene deletion and tagging, Genetics, 220
  71. D Peng, 2015, EuPaGDT: a web tool tailored to design CRISPR guide RNAs for eukaryotic pathogens., Microb Genom, 1, e000033
  72. Y Fan, 2018, Multiple Applications of a Transient CRISPR-Cas9 Coupled with Electroporation (TRACE) System in the Cryptococcus neoformans Species Complex., Genetics, 208, 1357, 10.1534/genetics.117.300656 · DOI
  73. KW Jung, 2018, Genetic Manipulation of Cryptococcus neoformans., Curr Protoc Microbiol, 50, e59, 10.1002/cpmc.59 · DOI
  74. D Gietz, 1992, Improved method for high efficiency transformation of intact yeast cells, Nucleic Acids Res, 20, 1425, 10.1093/nar/20.6.1425 · DOI
  75. R Tanaka, 1996, Determination of ploidy in Cryptococcus neoformans by flow cytometry, J Med Vet Mycol, 34, 299, 10.1080/02681219680000521 · DOI
  76. Q Dragotakes, 2018, Automated Measurement of Cryptococcal Species Polysaccharide Capsule and Cell Body., J Vis Exp, 10.3791/56957-v · DOI
  77. A Dobin, 2013, STAR: ultrafast universal RNA-seq aligner, Bioinformatics, 29, 15, 10.1093/bioinformatics/bts635 · DOI · Paper page
  78. Y Liao, 2014, featureCounts: an efficient general purpose program for assigning sequence reads to genomic features, Bioinformatics, 30, 923, 10.1093/bioinformatics/btt656 · DOI · Paper page
  79. MI Love, 2014, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol, 15, 550, 10.1186/s13059-014-0550-8 · DOI · Paper page
  80. S Babicki, 2016, Heatmapper: web-enabled heat mapping for all, Nucleic Acids Res, 44, W147, 10.1093/nar/gkw419 · DOI
  81. J Goedhart, 2020, VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots., Sci Rep., 10, 20560, 10.1038/s41598-020-76603-3 · DOI

Metadata

Authors
Peterson, P. P., Choi, J.-T., Fu, C., Cowen, L. E., Sun, S., Bahn, Y.-S., & Heitman, J.
Affiliations
  • Duke Medical Center (US)
  • Yonsei University (KR)
  • University of Toronto (CA)
Corresponding author
Heitman, Joseph
ORCID
Venue
PLOS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2024-11-19
Volume
20
Issue
11
Pages
e1012735
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1012735
PMC
PMC11614259
OpenAlex
W4404521637
Cited by
25
References
87
Citations by year
2026: 12 · 2025: 12 · 2024: 1
FWCI
7.58
Type
journal article
Language
en
Update notices
new_version (2024-12-03)
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Allergy and Infectious Diseases (T32 AI052080-20, R01 AI039115-27, R01 AI050113-20, R01 AI172451-02)
  • Canadian Institute for Health Research (FDN-154288)
  • Ministry of Science and ICT, South Korea (2021R1A2B5B03086596, 2021M3A9I4021434, 2018R1A5A1025077)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Cryptococcus neoformans, STRIPAK complex, genome stability, aneuploidy, sexual development, mating, virulence, heat tolerance, capsule production, melanization, calcineurin, cyclosporine, FK506, suppressor mutations

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