A gain-of-function mutation in PDR1 of Candida glabrata decreases EPA1 expression and attenuates adherence to epithelial cells through enhancing recruitment of the Mediator subunit Gal11A

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Genetic studies have revealed critical roles of transcription factor Pdr1 and the Mediator subunit Gal11A in regulating azole resistance in Candida glabrata. Recently, PDR1 gain-of-function (GOF) mutations have been shown to not only increase azole resistance but also enhance adherence during C. glabrata infection. However, mechanism of how Pdr1 regulates adherence, especially the implication of PDR1 GOF mutations in the regulation of the major adhesin gene EPA1, remains uncharacterized. Initially, we unexpectedly observed that expression of PDR1 harbouring GOF mutation G346D down-regulated EPA1 transcription and attenuated adherence to epithelial cells in different strain backgrounds. Given that PDR1 GOF mutations have been previously regarded as stimulators for adherence of this species, these findings prompted us to explore the regulation of EPA1 by wild-type Pdr1 and Pdr1 harbouring G346D mutation. Epitope tagged version of Pdr1 and Gal11A were utilized to determine the association of Pdr1 and Gal11A with EPA1 promoter. A combination of approaches including deletion, molecular, and biochemical assays showed that EPA1 is a direct target of Pdr1, and demonstrated for the first time that PDR1 G346D mutation decreases EPA1 expression and attenuates adherence to epithelial cells via enhancing recruitment of Gal11A. Taken together, our data propose a critical role of Gal11A in Pdr1-regulated EPA1 expression and adherence to epithelial cells, which could be utilized a novel therapeutic target for the treatment of hyper-adherent C. glabrata infection.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:239

Enthalten in:

Microbiological research - 239(2020) vom: 01. Okt., Seite 126519

Sprache:

Englisch

Beteiligte Personen:

Tian, Yuan [VerfasserIn]
Zhuang, Yihui [VerfasserIn]
Chen, Zhujun [VerfasserIn]
Mao, Yinhe [VerfasserIn]
Zhang, Jing [VerfasserIn]
Lu, Renquan [VerfasserIn]
Guo, Lin [VerfasserIn]

Links:

Volltext

Themen:

Candida glabrata
Epa1
Epithelial adhesin 1, Candida glabrata
Fungal Proteins
Gain-of-function mutation
Gal11A
Journal Article
Lectins
Pdr1
Transcription Factors

Anmerkungen:

Date Completed 15.07.2021

Date Revised 15.07.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.micres.2020.126519

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM311417604