Dokument: Regulators of hypoxic filamentation in the human fungal pathogen Candida albicans

Titel:	Regulators of hypoxic filamentation in the human fungal pathogen Candida albicans
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=50626
URN (NBN):	urn:nbn:de:hbz:061-20200917-091916-8
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Mr. Desai, Prashant Ramesh [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 73,83 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 26.08.2019 / geändert 26.08.2019
Beitragende:	Prof. Dr. Ernst, Joachim F. [Gutachter] Prof. Dr. Feldbrügge, Michael [Gutachter]
Stichwörter:	Candida albicans, hypoxia, transcription factors
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	The fungus Candida albicans is an important human pathogen that causes tenacious superficial infections, but also life-threatening systemic diseases. On the other hand, C. albicans resides as a harmless commensal in the human gastrointestinal (GI) tract. Its virulence depends largely on morphological transition from a commensal yeast form to a multicellular hyphal growth form, which invades tissues. This morphogenesis is regulated by environmental factors that in the human body frequently include oxygen-poor niches (hypoxia) containing elevated CO2 levels. The transcription factor Efg1 of C. albicans has a dual function, because it induces hyphal formation under normoxic conditions, but represses filamentation under hypoxia. Threonine residues 179 and 206 of Efg1 are phosphorylated for its normoxic function, while the native N-terminal region and non-phosphorylated threonine residues of Efg1 were found to be required for its function as a repressor under hypoxia. The genomic localization of Efg1 under hypoxia identified 300 target genes, which overlap with targets of transcription factors Ace2, Bcr1 and Brg1 that together form a regulatory hub regulating filamentation. Transcriptional analysis revealed that members of the Cek1-MAPK pathway of filamentation are repression targets of the Efg1 network to favour yeast growth under hypoxia. Furthermore, it was established that the function of Efg1 as the key morphogenetic regulator of C. albicans is regulated by additional novel mechanisms. Firstly, it was found that a 218 nt region within the 5´ untranslated region of the EFG1 transcript is important for its efficient translation. Also, it appears that phosphorylation of Efg1 already occurs at its target genes, because a part of the respective protein kinase A isoform Tpk2 co-localizes in the nucleus with Efg1. Previous results had established that the Sch9 kinase prevents hyphal morphogenesis of C. albicans under hypoxia, but only in the presence of high CO2 levels. To identify similarly acting regulators, a mutant library was screened that revealed 21 mutants growing in hyperfilamentous form under hypoxia and high CO2 levels, while 12 mutants were also unable to filament under normoxia (as an efg1 mutant). Transcript analysis of representative mutants lacking the Zcf14 or Crf1 proteins identified the UME6 gene, which encodes an essential positive regulator of filamentation, as the repression target. Collectively, the results indicate that C. albicans has a high potential to filament under hypoxia, but this ability is suppressed normally by a surprisingly high number of specific regulators. While hypoxic niches in the human host may generally favour yeast proliferation, controlled relief of filamentation repression may be instrumental in specific hypoxic niches, e.g. during escape from immune cells or for exit from the GI tract.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie
Dokument erstellt am:	17.09.2020
Dateien geändert am:	17.09.2020
Promotionsantrag am:	09.07.2019
Datum der Promotion:	22.08.2019