title: Dissection of Ire1 functions reveals stress response mechanisms uniquely evolved in Candida glabrata.
abstract: Proper protein folding in the endoplasmic reticulum (ER) is vital in all eukaryotes. When misfolded proteins accumulate in the ER lumen, the transmembrane kinase/endoribonuclease Ire1 initiates splicing of HAC1 mRNA to generate the bZIP transcription factor Hac1, which subsequently activates its target genes to increase the protein-folding capacity of the ER. This cellular machinery, called the unfolded protein response (UPR), is believed to be an evolutionarily conserved mechanism in eukaryotes. In this study, we comprehensively characterized mutant phenotypes of IRE1 and other related genes in the human fungal pathogen Candida glabrata. Unexpectedly, Ire1 was required for the ER stress response independently of Hac1 in this fungus. C. glabrata Ire1 did not cleave mRNAs encoding Hac1 and other bZIP transcription factors identified in the C. glabrata genome. Microarray analysis revealed that the transcriptional response to ER stress is not mediated by Ire1, but instead is dependent largely on calcineurin signaling and partially on the Slt2 MAPK pathway. The loss of Ire1 alone did not confer increased antifungal susceptibility in C. glabrata contrary to UPR-defective mutants in other fungi. Taken together, our results suggest that the canonical Ire1-Hac1 UPR is not conserved in C. glabrata. It is known in metazoans that active Ire1 nonspecifically cleaves and degrades a subset of ER-localized mRNAs to reduce the ER load. Intriguingly, this cellular response could occur in an Ire1 nuclease-dependent fashion in C. glabrata. We also uncovered the attenuated virulence of the C. glabrata Δire1 mutant in a mouse model of disseminated candidiasis. This study has unveiled the unique evolution of ER stress response mechanisms in C. glabrata.
authors: Department of Molecular Microbiology and Immunology, Nagasaki University School of Medicine, Nagasaki, Japan. taiga-m@nagasaki-u.ac.jp
authors: Taiga
authors: T
authors: Miyazaki
authors: Hironobu
authors: H
authors: Nakayama
authors: Yohsuke
authors: Y
authors: Nagayoshi
authors: Hiroshi
authors: H
authors: Kakeya
authors: Shigeru
authors: S
authors: Kohno
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin; D041221:Candida glabrata / Q000235:genetics* / Q000472:pathogenicity; D002177:Candidiasis / Q000235:genetics* / Q000382:microbiology / Q000401:mortality; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D004722:Endoribonucleases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007121:Immunocompetence; D020935:MAP Kinase Signaling System; D051379:Mice; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D012376:Rodent Diseases / Q000235:genetics* / Q000382:microbiology / Q000401:mortality; D020539:Sequence Analysis, Protein; D013045:Species Specificity; D015996:Survival Rate; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D012333:RNA, Messenger; D004722:Endoribonucleases; D019703:Calcineurin
references: Genes Cells. 1996 Sep;1(9):803-17
references: 9077435
references: Mol Biol Cell. 2009 Jan;20(1):164-75
references: 18971375
references: PLoS Pathog. 2011 Oct;7(10):e1002330
references: 22028661
references: Eukaryot Cell. 2008 Dec;7(12):2037-51
references: 18806210
references: Science. 2011 Nov 25;334(6059):1081-6
references: 22116877
references: Science. 1999 Aug 6;285(5429):901-6
references: 10436161
references: Am J Med. 2012 Jan;125(1 Suppl):S3-13
references: 22196207
references: PLoS Biol. 2006 Nov;4(12):e423
references: 17132049
references: J Cell Biol. 2011 Apr 4;193(1):41-50
references: 21444691
references: EMBO J. 1999 Jun 1;18(11):3119-32
references: 10357823
references: Nature. 2009 Feb 5;457(7230):687-93
references: 19079236
references: J Cell Biol. 2009 Aug 10;186(3):323-31
references: 19651891
references: Mol Biol Cell. 1997 Oct;8(10):1845-62
references: 9348528
references: Genes Cells. 2004 Feb;9(2):95-104
references: 15009095
references: G3 (Bethesda). 2012 Jun;2(6):675-91
references: 22690377
references: Cell. 2000 Apr 28;101(3):249-58
references: 10847680
references: Cell. 2009 Aug 7;138(3):562-75
references: 19665977
references: Science. 2006 Jul 7;313(5783):104-7
references: 16825573
references: FEMS Yeast Res. 2010 May;10(3):343-52
references: 20214686
references: Virulence. 2011 Jan-Feb;2(1):12-21
references: 21217201
references: Cell. 1993 Jun 18;73(6):1197-206
references: 8513503
references: J Biol Chem. 2006 Oct 6;281(40):30299-304
references: 16901900
references: J Biol Chem. 2010 Jun 25;285(26):20088-96
references: 20430884
references: Mol Biol Cell. 2003 Oct;14(10):4296-305
references: 14517337
references: Genetics. 1999 Mar;151(3):979-87
references: 10049916
references: Yeast. 2010 Jul;27(7):443-52
references: 20162530
references: Genes Cells. 2006 Jan;11(1):59-69
references: 16371132
references: Curr Biol. 1997 Nov 1;7(11):850-9
references: 9382810
references: Biostatistics. 2003 Apr;4(2):249-64
references: 12925520
references: Science. 2011 Sep 30;333(6051):1891-4
references: 21852455
references: Clin Microbiol Rev. 2007 Jan;20(1):133-63
references: 17223626
references: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references: 12582260
references: Microb Cell Fact. 2010 Jun 30;9:49
references: 20591165
references: Annu Rev Cell Dev Biol. 2006;22:487-508
references: 16822172
references: Fungal Genet Biol. 2008 Sep;45(9):1235-47
references: 18602013
references: J Cell Biol. 2006 Jan 30;172(3):383-93
references: 16449189
references: Bioinformatics. 2004 Dec 12;20(18):3710-5
references: 15297299
references: EMBO J. 1992 Jul;11(7):2583-93
references: 1628622
references: Cell. 2001 Oct 5;107(1):103-14
references: 11595189
references: J Clin Invest. 2002 Nov;110(10):1389-98
references: 12438434
references: Cell. 1996 Nov 1;87(3):391-404
references: 8898193
references: Gene. 2000 Apr 4;246(1-2):151-5
references: 10767536
references: Cell. 2008 Jan 11;132(1):89-100
references: 18191223
references: Mol Cell Biol. 1993 Feb;13(2):877-90
references: 8423809
references: Nature. 2004 Jul 1;430(6995):35-44
references: 15229592
references: Nat Rev Mol Cell Biol. 2008 Dec;9(12):944-57
references: 19002207
references: Cell. 2001 Dec 28;107(7):881-91
references: 11779464
references: RNA Biol. 2011 Jul-Aug;8(4):552-6
references: 21593604
references: J Cell Biol. 2010 May 31;189(5):783-94
references: 20513765
references: J Cell Biol. 2011 Apr 4;193(1):171-84
references: 21444684
references: FEMS Yeast Res. 2011 Aug;11(5):449-56
references: 21501380
references: EMBO J. 1996 Jun 17;15(12):3028-39
references: 8670804
references: J Biol Chem. 2004 May 14;279(20):20663-71
references: 15016820
references: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14343-8
references: 16973740
references: Cell. 1993 Aug 27;74(4):743-56
references: 8358794
references: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18773-84
references: 16365312
references: Cold Spring Harb Perspect Biol. 2012 Jun 01;4(6):
references: 22535228
references: Mol Microbiol. 2003 Feb;47(4):1149-61
references: 12581366
references: J Cell Sci. 2000 Nov;113 Pt 21:3697-702
references: 11034898
references: Cell. 1997 Sep 19;90(6):1031-9
references: 9323131
references: J Cell Biol. 2012 Jun 25;197(7):857-67
references: 22733998
references: J Biol Chem. 2002 Aug 23;277(34):31079-88
references: 12058033
references: J Biochem. 2009 Dec;146(6):743-50
references: 19861400
references: Genes Dev. 1999 May 15;13(10):1211-33
references: 10346810
references: EMBO J. 2002 May 15;21(10):2343-53
references: 12006487
references: J Clin Microbiol. 1998 Sep;36(9):2609-12
references: 9705401
references: PLoS Pathog. 2010 Feb 05;6(2):e1000752
references: 20140194
references: Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20597-602
references: 22143797
references: Cell. 2010 Jul 23;142(2):256-69
references: 20619447
references: Cell. 2012 Jun 8;149(6):1339-52
references: 22682253
references: J Biol Chem. 1998 Apr 17;273(16):9912-20
references: 9545334
references: J Dent Res. 2007 Mar;86(3):204-15
references: 17314251
references: Diagn Microbiol Infect Dis. 2011 Jan;69(1):45-50
references: 21146713
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references: 17565364
references: Cell. 1996 Nov 1;87(3):405-13
references: 8898194
references: Mol Cancer Res. 2005 Dec;3(12):669-77
references: 16380504
references: Nature. 2002 Jan 3;415(6867):92-6
references: 11780124
references: Cell. 2001 Dec 28;107(7):893-903
references: 11779465
references: PLoS Pathog. 2011 Mar;7(3):e1001322
references: 21445236
references: PLoS Pathog. 2011 Aug;7(8):e1002177
references: 21852949
references: EMBO J. 2007 Jan 10;26(1):242-52
references: 17170705
references: Antimicrob Agents Chemother. 2010 Apr;54(4):1639-43
references: 20100876
references: Science. 2003 Nov 28;302(5650):1533-7
references: 14564015
references: PLoS Pathog. 2009 Jan;5(1):e1000258
references: 19132084
references: Nat Rev Mol Cell Biol. 2003 Mar;4(3):181-91
references: 12612637