title: KRE5 Suppression Induces Cell Wall Stress and Alternative ER Stress Response Required for Maintaining Cell Wall Integrity in Candida glabrata.
abstract: The maintenance of cell wall integrity in fungi is required for normal cell growth, division, hyphae formation, and antifungal tolerance. We observed that endoplasmic reticulum stress regulated cell wall integrity in Candida glabrata, which possesses uniquely evolved mechanisms for unfolded protein response mechanisms. Tetracycline-mediated suppression of KRE5, which encodes a predicted UDP-glucose:glycoprotein glucosyltransferase localized in the endoplasmic reticulum, significantly increased cell wall chitin content and decreased cell wall β-1,6-glucan content. KRE5 repression induced endoplasmic reticulum stress-related gene expression and MAP kinase pathway activation, including Slt2p and Hog1p phosphorylation, through the cell wall integrity signaling pathway. Moreover, the calcineurin pathway negatively regulated cell wall integrity, but not the reduction of β-1,6-glucan content. These results indicate that KRE5 is required for maintaining both endoplasmic reticulum homeostasis and cell wall integrity, and that the calcineurin pathway acts as a regulator of chitin-glucan balance in the cell wall and as an alternative mediator of endoplasmic reticulum stress in C. glabrata.
authors.affiliation: Department of Infection and Host Defense, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
authors.forename: Yutaka
authors.identifier: http://orcid.org/0000-0003-2944-8485
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Infection and Host Defense, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Department of Infection and Host Defense, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Ito
authors.affiliation: Department of Electronic and Information Engineering, Suzuka National College of Technology, Suzuka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Aoyama
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Sato-Okamoto
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Takahashi-Nakaguchi
authors.affiliation: Medical Mycology Research Center, Chiba University, Chiba, Japan.
authors.forename: Hiroji
authors.initials: H
authors.lastname: Chibana
authors.affiliation: Department of Infection and Host Defense, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shibata
mesh_terms: D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D041221:Candida glabrata / Q000737:chemistry / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002473:Cell Wall / Q000737:chemistry / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002686:Chitin / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D025301:Hyphae / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D047071:beta-Glucans / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D047071:beta-Glucans; D002686:Chitin; C064197:beta-1,6-glucan; D005964:Glucosyltransferases; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin; D013752:Tetracycline