Abstract
The basis for commitment to cell division in late G1 phase, called Start in yeast, is a critical but still poorly understood aspect of eukaryotic cell proliferation. Most dividing cells accumulate mass and grow to a critical cell size before traversing the cell cycle. This size threshold couples cell growth to division and thereby establishes long-term size homeostasis. At present, mechanisms involved in cell size homeostasis in fungal pathogens are not well described. Our previous survey of the size phenome in Candida albicans focused on 279 unique mutants enriched mainly in kinases and transcription factors (Sellam et al. PLoS Genet 15:e1008052, 2019). To uncover novel size regulators in C. albicans and highlight potential innovation within cell size control in pathogenic fungi, we expanded our genetic survey of cell size to include 1301 strains from the GRACE (Gene Replacement and Conditional Expression) collection. The current investigation uncovered both known and novel biological processes required for cell size homeostasis in C. albicans. We also confirmed the plasticity of the size control network as few C. albicans size genes overlapped with those of the budding yeast Saccharomyces cerevisiae. Many new size genes of C. albicans were associated with biological processes that were not previously linked to cell size control and offer an opportunity for future investigation. Additional work is needed to understand if mitochondrial activity is a critical element of the metric that dictates cell size in C. albicans and whether modulation of the onset of actomyosin ring constriction is an additional size checkpoint.
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References
Berman J (2006) Morphogenesis and cell cycle progression in Candida albicans. Curr Opin Microbiol 9:595–601. https://doi.org/10.1016/j.mib.2006.10.007
Björklund M (2019) Cell size homeostasis: metabolic control of growth and cell division. Biochim Biophys Acta (BBA) Mol Cell Res 1866:409–417. https://doi.org/10.1016/j.bbamcr.2018.10.002
Blank HM, Li C, Mueller JE et al (2008) An increase in mitochondrial DNA promotes nuclear DNA replication in yeast. PLoS Genet 4:e1000047. https://doi.org/10.1371/journal.pgen.1000047
Blank HM, Callahan M, Pistikopoulos IPE et al (2018) Scaling of G1 duration with population doubling time by a cyclin in Saccharomyces cerevisiae. Genetics 210:895–906. https://doi.org/10.1534/genetics.118.301507
Blankenship JR, Fanning S, Hamaker JJ, Mitchell AP (2010) An extensive circuitry for cell wall regulation in Candida albicans. PLoS Pathog 6:e1000752. https://doi.org/10.1371/journal.ppat.1000752
Branzk N, Lubojemska A, Hardison SE et al (2014) Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol 15:1017–1025. https://doi.org/10.1038/ni.2987
Chaillot J, Cook MA, Corbeil J, Sellam A (2017) Genome-wide screen for haploinsufficient cell size genes in the opportunistic yeast Candida albicans. G3 (bethesda) 7:355–360. https://doi.org/10.1534/g3.116.037986
Chaillot J, Tebbji F, Mallick J, Sellam A (2019) Integration of growth and cell size via the TOR pathway and the Dot6 transcription factor in Candida albicans. Genetics 211:637–650. https://doi.org/10.1534/genetics.118.301872
Chaillot J, Mallick J, Sellam A (2022) The transcription factor Ahr1 links cell size control to amino acid metabolism in the opportunistic yeast Candida albicans. Biochem Biophys Res Commun 616:63–69. https://doi.org/10.1016/j.bbrc.2022.05.074
Cheffings TH, Burroughs NJ, Balasubramanian MK (2016) Actomyosin ring formation and tension generation in eukaryotic cytokinesis. Curr Biol 26:R719–R737. https://doi.org/10.1016/j.cub.2016.06.071
Cook M, Tyers M (2007) Size control goes global. Curr Opin Biotechnol 18:341–350. https://doi.org/10.1016/j.copbio.2007.07.006
Costanzo M, Nishikawa JL, Tang X et al (2004) CDK activity antagonizes Whi5, an inhibitor of G1/S transcription in yeast. Cell 117:899–913. https://doi.org/10.1016/j.cell.2004.05.024
Cote P, Hogues H, Whiteway M (2009) Transcriptional analysis of the Candida albicans cell cycle. Mol Biol Cell 20:3363–3373. https://doi.org/10.1091/mbc.E09-03-0210
de Bruin RA, McDonald WH, Kalashnikova TI et al (2004) Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5. Cell 117:887–898. https://doi.org/10.1016/j.cell.2004.05.025
Dorsey S, Tollis S, Cheng J et al (2018) G1/S transcription factor copy number is a growth-dependent determinant of cell cycle commitment in yeast. Cell Syst 6:539-554.e11. https://doi.org/10.1016/j.cels.2018.04.012
Fisher RP (2021) A cell cycle regulator branches out. Science 374:263–264. https://doi.org/10.1126/science.abm2010
Harvey SL, Kellogg DR (2003) Conservation of mechanisms controlling entry into mitosis: budding yeast wee1 delays entry into mitosis and is required for cell size control. Curr Biol 13:264–275. https://doi.org/10.1016/s0960-9822(03)00049-6
Hommel B, Mukaremera L, Cordero RJB et al (2018) Titan cells formation in Cryptococcus neoformans is finely tuned by environmental conditions and modulated by positive and negative genetic regulators. PLoS Pathog 14:e1006982. https://doi.org/10.1371/journal.ppat.1006982
Jorgensen P, Tyers M (2004) How cells coordinate growth and division. Curr Biol 14:R1014–R1027. https://doi.org/10.1016/j.cub.2004.11.027
Jorgensen P, Nishikawa JL, Breitkreutz BJ, Tyers M (2002) Systematic identification of pathways that couple cell growth and division in yeast. Science 297:395–400. https://doi.org/10.1126/science.1070850
Jorgensen P, Rupes I, Sharom JR et al (2004) A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev 18:2491–2505. https://doi.org/10.1101/gad.1228804
Juanes MA, Piatti S (2016) The final cut: cell polarity meets cytokinesis at the bud neck in S. cerevisiae. Cell Mol Life Sci 73:3115–3136. https://doi.org/10.1007/s00018-016-2220-3
Kõivomägi M, Swaffer MP, Turner JJ et al (2021) G1 cyclin–Cdk promotes cell cycle entry through localized phosphorylation of RNA polymerase II. Science 374:347–351. https://doi.org/10.1126/science.aba5186
Lavoie H, Hogues H, Whiteway M (2009) Rearrangements of the transcriptional regulatory networks of metabolic pathways in fungi. Curr Opin Microbiol 12:655–663. https://doi.org/10.1016/j.mib.2009.09.015
Lenski RE, Travisano M (1994) Dynamics of adaptation and diversification: a 10,000-generation experiment with bacterial populations. Proc Natl Acad Sci U S A 91:6808–6814. https://doi.org/10.1073/pnas.91.15.6808
Li H, Johnson AD (2010) Evolution of transcription networks–lessons from yeasts. Curr Biol 20:R746–R753. https://doi.org/10.1016/j.cub.2010.06.056
Litsios A, Huberts DHEW, Terpstra HM et al (2019) Differential scaling between G1 protein production and cell size dynamics promotes commitment to the cell division cycle in budding yeast. Nat Cell Biol 21:1382–1392. https://doi.org/10.1038/s41556-019-0413-3
Liu S, Ginzberg MB, Patel N et al (2018) Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length. Elife 7:e26947. https://doi.org/10.7554/eLife.26947
Lloyd AC (2013) The regulation of cell size. Cell 154:1194–1205. https://doi.org/10.1016/j.cell.2013.08.053
Miettinen TP, Björklund M (2016) Cellular allometry of mitochondrial functionality establishes the optimal cell size. Dev Cell 39:370–382. https://doi.org/10.1016/j.devcel.2016.09.004
Roemer T, Jiang B, Davison J et al (2003) Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Mol Microbiol 50:167–181. https://doi.org/10.1046/j.1365-2958.2003.03697.x
Rossio V, Yoshida S (2011) Spatial regulation of Cdc55–PP2A by Zds1/Zds2 controls mitotic entry and mitotic exit in budding yeast. J Cell Biol 193:445–454. https://doi.org/10.1083/jcb.201101134
Salichos L, Rokas A (2013) Inferring ancient divergences requires genes with strong phylogenetic signals. Nature 497:327–331. https://doi.org/10.1038/nature12130
Schmoller KM, Turner JJ, Kõivomägi M, Skotheim JM (2015) Dilution of the cell cycle inhibitor Whi5 controls budding-yeast cell size. Nature 526:268–272. https://doi.org/10.1038/nature14908
Schmoller KM, Lanz MC, Kim J et al (2022) Whi5 is diluted and protein synthesis does not dramatically increase in pre-Start G1. MBoC. 33:lt1. https://doi.org/10.1091/mbc.E21-01-0029
Sellam A, Chaillot J, Mallick J et al (2019) The p38/HOG stress-activated protein kinase network couples growth to division in Candida albicans. PLoS Genet 15:e1008052. https://doi.org/10.1371/journal.pgen.1008052
Soifer I, Barkai N (2014) Systematic identification of cell size regulators in budding yeast. Mol Syst Biol 10:761. https://doi.org/10.15252/msb.20145345
Sommer RA, DeWitt JT, Tan R, Kellogg DR (2021) Growth-dependent signals drive an increase in early G1 cyclin concentration to link cell cycle entry with cell growth. Elife 10:e64364. https://doi.org/10.7554/eLife.64364
Turner JJ, Ewald JC, Skotheim JM (2012) Cell size control in yeast. Curr Biol 22:R350–R359. https://doi.org/10.1016/j.cub.2012.02.041
Tyers M (2004) Cell cycle goes global. Curr Opin Cell Biol 16:602–613. https://doi.org/10.1016/j.ceb.2004.09.013
Tyers M, Tokiwa G, Futcher B (1993) Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. EMBO J 12:1955–1968. https://doi.org/10.1002/j.1460-2075.1993.tb05845.x
Tyson CB, Lord PG, Wheals AE (1979) Dependency of size of Saccharomyces cerevisiae cells on growth rate. J Bacteriol 138:92–98. https://doi.org/10.1128/jb.138.1.92-98.1979
Wang L, Lin X (2012) Morphogenesis in fungal pathogenicity: shape, size, and surface. PLoS Pathog 8:e1003027. https://doi.org/10.1371/journal.ppat.1003027
Wood E, Nurse P (2015) Sizing up to divide: mitotic cell-size control in fission yeast. Annu Rev Cell Dev Biol 31:11–29. https://doi.org/10.1146/annurev-cellbio-100814-125601
Xie S, Swaffer M, Skotheim JM (2022) Eukaryotic cell size control and its relation to biosynthesis and senescence. Annu Rev Cell Dev Biol 38:291–319. https://doi.org/10.1146/annurev-cellbio-120219-040142
Zaragoza O, Nielsen K (2013) Titan cells in Cryptococcus neoformans: cells with a giant impact. Curr Opin Microbiol 16:409–413. https://doi.org/10.1016/j.mib.2013.03.006
Acknowledgements
We thank the National Research Council (NRC) Canada for providing the GRACE mutant collection.
Funding
This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC discovery grant) to AS. AS is supported by the Fonds de Recherche du Québec -Santé J2 salary award.
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All authors contributed to the study conception and design. JC and AS: performed the genetic size screen and wrote the manuscript draft. MAC: generated R scripts for data analysis. All authors read and approved the final manuscript.
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294_2022_1260_MOESM1_ESM.xlsx
Supplementary file1 Excel spreadsheet containing experimental size data of individual mutant from the C. albicans GRACE collection. Mean, median and mode size of each strain are shown (XLSX 79 KB)
294_2022_1260_MOESM2_ESM.xlsx
Supplementary file2 Excel spreadsheet listing C. albicans size mutants. Mutants for whom median size was increased or decreased by 20% as compared to the parental WT strains are indicated (XLSX 19 KB)
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Chaillot, J., Cook, M.A. & Sellam, A. Novel determinants of cell size homeostasis in the opportunistic yeast Candida albicans. Curr Genet 69, 67–75 (2023). https://doi.org/10.1007/s00294-022-01260-0
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DOI: https://doi.org/10.1007/s00294-022-01260-0