title: Candida albicans flu1-mediated efflux of salivary histatin 5 reduces its cytosolic concentration and fungicidal activity.
abstract: Histatin 5 (Hst 5) is a salivary human antimicrobial peptide that is toxic to the opportunistic yeast Candida albicans. Fungicidal activity of Hst 5 requires intracellular translocation and accumulation to a threshold concentration for it to disrupt cellular processes. Previously, we observed that total cytosolic levels of Hst 5 were gradually reduced from intact cells, suggesting that C. albicans possesses a transport mechanism for efflux of Hst 5. Since we identified C. albicans polyamine transporters responsible for Hst 5 uptake, we hypothesized that one or more polyamine efflux transporters may be involved in the efflux of Hst 5. C. albicans FLU1 and TPO2 were found to be the closest homologs of Saccharomyces cerevisiae TPO1, which encodes a major spermidine efflux transporter, indicating that the products of these two genes may be involved in efflux of Hst 5. We found that flu1Δ/Δ cells, but not tpo2Δ/Δ cells, had significant reductions in their rates of Hst 5 efflux and had significantly higher cytoplasmic Hst 5 and Hst 5 susceptibilities than did the wild type. We also found that flu1Δ/Δ cells had reduced biofilm formation compared to wild-type cells in the presence of Hst 5. Transcriptional levels of FLU1 were not altered over the course of treatment with Hst 5; therefore, Hst 5 is not likely to induce FLU1 gene overexpression as a potential mechanism of resistance. Thus, Flu1, but not Tpo2, mediates efflux of Hst 5 and is responsible for reduction of its toxicity in C. albicans.
authors: Department of Oral Biology, University at Buffalo, Buffalo, New York, USA.
authors: Rui
authors: R
authors: Li
authors: Rohitashw
authors: R
authors: Kumar
authors: Swetha
authors: S
authors: Tati
authors: Sumant
authors: S
authors: Puri
authors: Mira
authors: M
authors: Edgerton
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000235:genetics; D005656:Fungal Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D054808:Histatins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010802:Phylogeny; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013095:Spermidine / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; C417782:FLU1 protein, Candida albicans; D005656:Fungal Proteins; C068075:HTN3 protein, human; D054808:Histatins; D013095:Spermidine
references: Oral Dis. 1997 May;3 Suppl 1:S102-9
references: 9456667
references: Med Mycol. 2005 May;43(3):235-43
references: 16010850
references: Arch Oral Biol. 2009 Jun;54(6):588-94
references: 19249746
references: Microbiology (Reading). 2011 Apr;157(Pt 4):945-956
references: 21148207
references: Antimicrob Agents Chemother. 1996 Oct;40(10):2300-5
references: 8891134
references: Eur Rev Med Pharmacol Sci. 2004 Mar-Apr;8(2):69-77
references: 15267120
references: Clin Infect Dis. 2004 Aug 1;39(3):309-17
references: 15306996
references: Biochem J. 2001 Feb 1;353(Pt 3):681-8
references: 11171066
references: Med Mycol. 2002 Feb;40(1):73-81
references: 11860016
references: Diagn Microbiol Infect Dis. 2004 Sep;50(1):25-32
references: 15380275
references: Microbiol Mol Biol Rev. 2011 Jun;75(2):213-67
references: 21646428
references: Eukaryot Cell. 2009 Jun;8(6):806-20
references: 19395663
references: Nat Rev Microbiol. 2008 Mar;6(3):187-98
references: 18246082
references: Microbiology (Reading). 1997 Feb;143 ( Pt 2):405-416
references: 9043118
references: J Biol Chem. 2002 Jul 26;277(30):27036-44
references: 12016207
references: Antimicrob Agents Chemother. 2008 Feb;52(2):497-504
references: 17999963
references: J Biol Chem. 2004 Oct 1;279(40):41436-43
references: 15272024
references: Gene. 2001 Jul 11;272(1-2):111-9
references: 11470516
references: Eukaryot Cell. 2008 May;7(5):747-64
references: 18375617
references: Clin Infect Dis. 2003 Nov 1;37(9):1172-7
references: 14557960
references: Genetics. 1993 Jul;134(3):717-28
references: 8349105
references: Mol Microbiol. 2012 Dec;86(6):1295-317
references: 23106164
references: J Amino Acids. 2012;2012:837932
references: 22957208
references: Antimicrob Agents Chemother. 1997 Jul;41(7):1482-7
references: 9210670
references: J Biol Chem. 2005 Mar 11;280(10):9646-52
references: 15637075
references: Nat Rev Drug Discov. 2010 Sep;9(9):719-27
references: 20725094
references: Antimicrob Agents Chemother. 1995 Nov;39(11):2378-86
references: 8585712
references: Eukaryot Cell. 2007 Mar;6(3):443-53
references: 17209122
references: Eukaryot Cell. 2003 Dec;2(6):1361-75
references: 14665469
references: J Clin Microbiol. 2005 Apr;43(4):1829-35
references: 15815004
references: Nat Rev Microbiol. 2005 Jul;3(7):547-56
references: 15953931
references: Clin Infect Dis. 2006 Jan 15;42(2):244-51
references: 16355336
references: Cell Mol Life Sci. 2005 Dec;62(24):3106-16
references: 16374585
references: Clin Microbiol Rev. 2009 Apr;22(2):291-321, Table of Contents
references: 19366916
references: PLoS Pathog. 2010 Sep 30;6(9):e1001126
references: 20941354
references: Antimicrob Agents Chemother. 1997 Oct;41(10):2224-8
references: 9333052
references: Arch Biochem Biophys. 1991 Mar;285(2):306-11
references: 1832828
references: OMICS. 2010 Dec;14(6):701-10
references: 21114408
references: Curr Genet. 1995 Mar;27(4):320-9
references: 7614555
references: Antimicrob Agents Chemother. 1998 Nov;42(11):2932-7
references: 9797228
references: J Biol Chem. 2011 Dec 23;286(51):43748-43758
references: 22033918
references: FEMS Microbiol Lett. 1997 Apr 15;149(2):141-9
references: 9141655
references: J Biol Chem. 1990 Mar 5;265(7):3898-905
references: 2406266
references: Science. 1996 Oct 25;274(5287):546, 563-7
references: 8849441
references: FEBS Lett. 1995 Dec 18;377(2):232-6
references: 8543057
references: Fungal Genet Biol. 2010 Feb;47(2):94-106
references: 19665571
references: J Biol Chem. 2003 Aug 1;278(31):28553-61
references: 12761219
references: Mol Microbiol. 2010 Jul;77(2):354-70
references: 20487276
references: Infect Immun. 2000 Dec;68(12):6848-56
references: 11083804
references: Microbiology (Reading). 2000 Nov;146 ( Pt 11):2743-2754
references: 11065353
references: Biochem Soc Trans. 1991 Aug;19(3):782-7
references: 1783216
references: J Int Med Res. 2010 Mar-Apr;38(2):536-45
references: 20515567
references: Trends Microbiol. 1994 Oct;2(10):393-400
references: 7850208
references: Eukaryot Cell. 2007 Oct;6(10):1876-88
references: 17715369
references: J Biol Chem. 1999 Feb 5;274(6):3265-7
references: 9920864
references: J Dent Res. 1999 Jun;78(6):1245-50
references: 10371248
references: Microbiology (Reading). 2007 Oct;153(Pt 10):3211-3217
references: 17906120
references: Methods Mol Biol. 2011;720:295-308
references: 21318881
references: Antimicrob Agents Chemother. 2001 Oct;45(10):2676-84
references: 11557454