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The tricarboxylic acid cycle, cell wall integrity pathway, cytokinesis and intracellular pH homeostasis are involved in the sensitivity of Candida albicans cells to high levels of extracellular calcium


The tricarboxylic acid cycle, cell wall integrity pathway, cytokinesis and intracellular pH homeostasis are involved in the sensitivity of Candida albicans cells to high levels of extracellular calcium

Whiteway, Malcolm, Xu, Huihui and Jiang, Linghuo (2018) The tricarboxylic acid cycle, cell wall integrity pathway, cytokinesis and intracellular pH homeostasis are involved in the sensitivity of Candida albicans cells to high levels of extracellular calcium. Genomics . ISSN 08887543 (In Press)

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Official URL: http://dx.doi.org/10.1016/j.ygeno.2018.08.001


Through a genetic screen we have identified 21 genes whose inactivation renders Candida albicans cells sensitive to high levels of extracellular calcium. These genes are involved in the tricarboxylic acid cycle, cell wall integrity pathway, cytokinesis, intracellular pH homeostasis, magnesium transport, as well as DNA damage response and repair processes. The calcium sensitivity due to inactivation of nine of these genes can be partially or completely suppressed by cyclosporine A, an inhibitor of calcineurin. Therefore, the calcium sensitivity of nearly a half of these 21 mutations is at least partially due to the activation of calcium/calcineurin signaling. Our work provides a basis for further understanding the regulation of calcium homeostasis in this important human fungal pathogen.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Article
Authors:Whiteway, Malcolm and Xu, Huihui and Jiang, Linghuo
Journal or Publication:Genomics
Date:22 May 2018
  • National Natural Science Foundation of China
Digital Object Identifier (DOI):10.1016/j.ygeno.2018.08.001
Keywords:GRACE, calcium; Screen, calcineurin; Yeast
ID Code:984185
Deposited By: ALINE SOREL
Deposited On:22 Aug 2018 15:53
Last Modified:10 Aug 2019 00:00


J. Alber, L. Jiang, J. Geyer. CaRch1p does not functionally interact with the high-affinity Ca2+ influx system (HACS) of Candida albicans, Yeast, 30 (2013), pp. 449-457

M. Azuma, J.N. Levinson, N. Pagé, H. Bussey. Saccharomyces cerevisiae Big1p, a putative endoplasmic reticulum membrane protein required for normal levels of cell wall beta-1,6-glucan, Yeast, 19 (2002), pp. 783-793

B. Baro, J.A. Rodriguez-Rodriguez, I. Calabria, M.L. Hernaez, C. Gil, E. Queralt. Dual regulation of the mitotic exit network (MEN) by PP2A-Cdc55 phosphatase, PLoS Genet., 9 (12) (2013), Article e1003966

S. Bates, D.M. MacCallum, G. Bertram, C.A. Munro, H.B. Hughes, E.T. Buurman, A.J. Brown, F.C. Odds, N.A. Gow. Candida albicans Pmr1p, a secretory pathway P-type Ca2+/Mn2+-ATPase, is required for glycosylation and virulence, J. Biol. Chem., 280 (2005), pp. 23408-23415

J.M. Becker, S.J. Kauffman, M. Hauser, L. Huang, M. Lin, S. Sillaots, B. Jiang, D. Xu, T. Roemer. Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model, Proc. Natl. Acad. Sci. U. S. A., 107 (2010), pp. 22044-22049

M. Bermudez-Lopez, A. Ceschia, G. de Piccoli, N. Colomina, P. Pasero, L. Aragón, J. Torres-Rosell. The Smc5/6 complex is required for dissolution of DNA-mediated sister chromatid linkages, Nucleic Acids Res., 38 (2010), pp. 6502-6512

R. Bond, N. Ly, M.S. Cyert. The unique C terminus of the calcineurin isoform CNAβ1 confers non-canonical regulation of enzyme activity by Ca2+ and calmodulin, J. Biol. Chem., 292 (2017), pp. 16709-16721

N. Chauhan, J.P. Latge, R. Calderone. Signalling and oxidant adaptation in Candida albicans and Aspergillus fumigatus, Nat. Rev. Microbiol., 4 (2006), pp. 435-444

X.J. Chen, X. Wang, B.A. Kaufman, R.A. Butow. Aconitase couples metabolic regulation to mitochondrial DNA maintenance, Science, 307 (2005), pp. 714-717
Y. Chen, J. Mallick, A. Maqnas, Y. Sun, B.I. Choudhury, P. Cote, L. Yan, T.J. Ni, Y. Li, D. Zhang, R. Rodríguez-Ortiz, Q.Z. Lv, Y.Y. Jiang, M. Whiteway. Chemogenomic profiling of the fungal P\pathogen Candida albicans, Antimicrob Agents Chemother., 62 (2) (2018) (pii: e02365–17)

A.S. Colinet, L. Thines, A. Deschamps, G. Flemal, D. Demaegd, P. Morsomme. Acidic and uncharged polar residues in the consensus motifs of the yeast Ca2+ transporter Gdt1p are required for calcium transport, Cell Microbiol., 19 (7) (2017), 10.1111/cmi.12729

M.C. Cruz, A.L. Goldstein, J.R. Blankenship, M. Del Poeta, D. Davis, M.E. Cardenas, J.R. Perfect, J.H. McCusker, J. Heitman. Calcineurin is essential for survival during membrane stress in Candida albicans, EMBO J., 21 (2002), pp. 546-559

J. Cui, J.A. Kaandorp, P.M. Sloot, C.M. Lloyd, M.V. Filatov. Calcium homeostasis and signaling in yeast cells and cardiac myocytes, FEMS Yeast Res., 9 (2009), pp. 1137-1147

J. Cui, J.A. Kaandorp, O.O. Ositelu, V. Beaudry, A. Knight, Y.F. Nanfack, K.W. Cunningham. Simulating calcium influx and free calcium concentrations in yeast, Cell Calcium, 45 (2009), pp. 123-132

J.R. Cupp, L. McAlister-Henn. Cloning and characterization of the gene encoding the IDH1 subunit of NAD (+)-dependent isocitrate dehydrogenase from Saccharomyces cerevisiae, J. Biol. Chem., 267 (1992), pp. 16417-16423

M.S. Cyert, C.C. Philpott. Regulation of cation balance in Saccharomyces cerevisiae, Genetics, 193 (2013), pp. 677-713

M.S. Cyert(2003). Calcineurin signaling in Saccharomyces cerevisiae: how yeast go crazy in response to stress, Biochem. Biophys. Res. Commun., 311 (2003), pp. 1143-1150

M. Dadar, R. Tiwari, K. Karthik, S. Chakraborty, Y. Shahali, K. Dhama. Candida albicans - biology, molecular characterization, pathogenicity, and advances in diagnosis and control - an update, Microb. Pathog., 117 (2018), pp. 128-138

E.A. Espeso. The CRaZy calcium cycle, Adv. Exp. Med. Biol., 892 (2016), pp. 169-186

N.A. Gow, F.L. van de Veerdonk, A.J. Brown, M.G. Netea. Candida albicans morphogenesis and host defence: discriminating invasion from colonization, Nat. Rev. Microbiol., 10 (2011), pp. 112-122

A. Graschopf, J.A. Stadler, M.K. Hoellerer, S. Eder, M. Sieghardt, S.D. Kohlwein, R.J. Schweyen. The yeast plasma membrane protein Alr1 controls Mg2+ homeostasis and is subject to Mg2+-dependent control of its synthesis and degradation, J. Biol. Chem., 276 (2001), pp. 16216-16222

B.R. Graziano, H.Y. Yu, S.L. Alioto, J.A. Eskin, C.A. Ydenberg, D.P. Waterman, M. Garabedian, B.L. Goode. The F-BAR protein Hof1 tunes formin activity to sculpt actin cables during polarized growth, Mol. Biol. Cell, 25 (2014), pp. 1730-1743

N.C. Hoch, E.S. Chen, R. Buckland, S.C. Wang, A. Fazio, A. Hammet, A. Pellicioli, A. Chabes, M.D. Tsai, J. Heierhorst. Molecular basis of the essential s phase function of the rad53 checkpoint kinase, Mol. Cell. Biol., 33 (2013), pp. 3202-3213

L. Jiang, J. Wang, F. Asghar, N. Snyder, K.W. Cunningham. CaGdt1 plays a compensatory role for the calcium pump CaPmr1 in the regulation of calcium signaling and cell wall integrity signaling in Candida albicans, Cell Commun. Signal., 16 (2018), p. 33

L. Jiang, D. Xu, A. Hameed, T. FangBakr Ahmad Fazili a, Asghar F. The plasma membrane protein Rch1 and the Golgi/ER calcium pump Pmr1 have an additive effect on filamentation in Candida albicans, Fungal Genet. Biol., 115 (2018), pp. 1-8

L. Jiang, J. Alber, J. Wang, W. Du, X. Li, J. Geyer. The Candida albicans plasma membrane protein Rch1p a member of the vertebrate SLC10 carrier family, is a novel regulator of cytosolic Ca2+ homoeostasis, Biochem. J., 444 (2012), pp. 497-502

M. Karababa, E. Valentino, G. Pardini, A.T. Coste, J. Bille, D. Sanglard. CRZ1, a target of the calcineurin pathway in Candida albicans, Mol. Microbiol., 59 (2006), pp. 1429-1451

M. Koivomagi, E. Valk, R. Venta, A. Iofik, M. Lepiku, E.R. Balog, S.M. Rubin, D.O. Morgan, M. LoogCascades of multisite phosphorylation control Sic1 destruction at the onset of S phase, Nature, 480 (2011), pp. 128-131

P.R. Kraus, J. Heitman. Coping with stress: calmodulin and calcineurin in model and pathogenic fungi, Biochem. Biophys. Res. Commun., 311 (2003), pp. 1151-1157

W.Q. Li, N.Z. Zhong, J. He, Y.M. Li, L.J. Hou, H.M. Liu, C.Y. Xia, L.Z. Wang, Y.C. Lu. High ATP2A2 expression correlates with better prognosis of diffuse astrocytic tumor patients, Oncol. Rep., 37 (2017), pp. 2865-2874

X. Li, Y. Hou, L. Yue, S. Liu, J. Du, S. Sun. Potential targets for antifungal drug discovery based on growth and virulence in Candida albicans, Antimicrob. Agents Chemother., 59 (2015), pp. 5885-5891

S. Liu, Y. Hou, W. Liu, C. Lu, W. Wang, S. Sun. Components of the calcium-calcineurin signaling pathway in fungal cells and their potential as antifungal targets, Eukaryot. Cell, 14 (2015), pp. 324-334

T.T. Liu, R.E. Lee, K.S. Barker, R.E. Lee, L. Wei, R. Homayouni, P.D. Rogers. Genome-wide expression profiling of the response to azole, polyene, echinocandin, and pyrimidine antifungal agents in Candida albicans, Antimicrob. Agents Chemother., 49 (2005), pp. 2226-2236

K.F. Medler. Calcium signaling in taste cells: regulation required, Chem. Senses, 35 (2010), pp. 753-765

M.D. Metodiev, et al .Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy, J. Med. Genet., 51 (2014), pp. 834-838

C. Mille, G. Janbon, F. Delplace, S. Ibata-Ombetta, C. Gaillardin, G. Strecker, T. Jouault, P.A. Trinel, D. Poulain. Inactivation of CaMIT1 inhibits Candida albicans phospholipomannan beta-mannosylation, reduces virulence, and alters cell wall protein beta-mannosylation, J. Biol. Chem., 279 (2004), pp. 47952-47960

K. Obara, H. Yamamoto, A. Kihara. Membrane protein Rim21 plays a central role in sensing ambient pH in Saccharomyces cerevisiae, J. Biol. Chem., 287 (2012), pp. 38473-38481

S. Thewes. Calcineurin-Crz1 signaling in lower eukaryotes, Eukaryot. Cell, 13 (2014), pp. 694-705

T. Umeyama, A. Kaneko, Y. Nagai, N. Hanaoka, K. Tanabe, Y. Takano, M. Niimi, Y. Uehara. Candida albicans protein kinase CaHsl1p regulates cell elongation and virulence, Mol. Microbiol., 55 (2005), pp. 381-395

T. Umeyama, A. Kaneko, H. Watanabe, A. Hirai, Y. Uehara, M. Niimi, M. Azuma. Deletion of the CaBIG1 gene reduces beta-1,6-glucan synthesis, filamentation, adhesion, and virulence in Candida albicans, Infect. Immun., 74 (2006), pp. 2373-2381

Y. Wang, J. Wang, J. Cheng, D. Xu, L. Jiang. Genetic interactions between the Golgi Ca2+/H+ exchanger Gdt1 and the plasma membrane calcium channel Cch1/Mid1 in the regulation of calcium homeostasis, stress response and virulence in Candida albicans, FEMS Yeast Res., 15 (7) (2015) (pii: fov069)

R. Wightman, S. Bates, P. Amornrrattanapan, P. SudberyIn. Candida albicans, the Nim1 kinases Gin4 and Hsl1 negatively regulate pseudohypha formation and Gin4 also controls septin organization, J. Cell Biol., 164 (2004), pp. 581-591

K.E. Wilson, S.K. Smith, R. Kelly, P. Masurekar, D. Xu, C.A. Parish, H. Wang, D.L. Zink, J.E. Davies, T. Roemer. Discovery, isolation, and structure elucidation of dretamycin, J. Nat. Prod., 77 (2014), pp. 1280-1286

D. Xu, B. Jiang, T. Ketela, S. Lemieux, K. Veillette, N. Martel, J. Davison, S. Sillaots, S. Trosok, C. Bachewich, H. Bussey, P. Youngman, T. Roemer. Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albicans, PLoS Pathog., 3 (6) (2007), Article e92

D. Xu, J. Cheng, C. Cao, L. Wang, L. Jiang. Genetic interactions between Rch1 and the high-affinity calcium influx system Cch1/Mid1/Ecm7 in the regulation of calcium homeostasis, drug tolerance, hyphal development and virulence in Candida albicans, FEMS Yeast Res. (2015), 10.1093/femsyr/fov079

S.J. Yu, Y.L. Chang, Y.L. Chen. Calcineurin signaling: lessons from Candida species, FEMS Yeast Res., 15 (2015) (fov016)

L. Zhang, N. Liu, X. Ma, L. Jiang. The transcriptional control machinery as well as the cell wall integrity and its regulation are involved in the detoxification of the organic solvent dimethyl sulfoxide in Saccharomyces cerevisiae, FEMS Yeast Res., 13 (2013), pp. 200-218

J. Zhao, W. Lin, X. Ma, Q. Lu, X. Ma, G. Bian, L. Jiang. The protein kinase Hal5p is the high-copy suppressor of lithium-sensitive mutations of genes involved in sporulation and meiosis as well as ergosterol biosynthesis in Saccharomyces cerevisiae, Genomics, 95 (2010), pp. 290-298

Y. Zhao, J. Du, B. Xiong, H. Xu, L. Jiang. ESCRT components regulate the expression of the ER/Golgi calcium pump gene PMR1 through the Rim101/Nrg1 pathway in budding yeast, J. Mol. Cell Biol., 5 (2013), pp. 336-344

Y. Zhao, J. Du, G. Zhao, L. Jiang. Activation of calcineurin is mainly responsible for the calcium sensitivity of gene deletion mutations in the genome of budding yeast, Genomics, 101 (2013), pp. 49-56

Y. Zhao, H. Yan, R. Happeck, T. Peiter-Volk, H. Xu, Y. Zhang, E. Peiter, Triplet C. van Oostende, M. Whiteway, L. Jiang. The plasma membrane protein Rch1 is a negative regulator of cytosolic calcium homeostasis and positively regulated by the calcium/calcineurin signaling pathway in budding yeast, Eur. J. Cell Biol., 95 (2016), pp. 164-174

B.O. Zhou, S.S. Wang, L.X. Xu, F.L. Meng, Y.J. Xuan, Y.M. Duan, J.Y. Wang, H. Hu, X. Dong, J. Ding, J.Q. Zhou. SWR1 complex poises heterochromatin boundaries for antisilencing activity propagation, Mol. Cell. Biol., 30 (2010), pp. 2391-2400
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