The bZIP Transcription Factor Rca1p Is a Central Regulator of a Novel CO2 Sensing Pathway in Yeast

Fabien Cottier,Marianne Bolstad,Michael C Lorenz,Fritz A Mühlschlegel,Dominique Sanglard,Martine Raymond,Worraanong Leewattanapasuk,Claudia Jiménez-López,Libuše Váchová,Oliver Kurzai,Norman Pavelka,Zdena Palková

doi:10.1371/journal.ppat.1002485

Abstract

Like many organisms the fungal pathogen Candida albicans senses changes in the environmental CO2 concentration. This response involves two major proteins: adenylyl cyclase and carbonic anhydrase (CA). Here, we demonstrate that CA expression is tightly controlled by the availability of CO2 and identify the bZIP transcription factor Rca1p as the first CO2 regulator of CA expression in yeast. We show that Rca1p upregulates CA expression during contact with mammalian phagocytes and demonstrate that serine 124 is critical for Rca1p signaling, which occurs independently of adenylyl cyclase. ChIP-chip analysis and the identification of Rca1p orthologs in the model yeast Saccharomyces cerevisiae (Cst6p) point to the broad significance of this novel pathway in fungi. By using advanced microscopy we visualize for the first time the impact of CO2 build-up on gene expression in entire fungal populations with an exceptional level of detail. Our results present the bZIP protein Rca1p as the first fungal regulator of carbonic anhydrase, and reveal the existence of an adenylyl cyclase independent CO2 sensing pathway in yeast. Rca1p appears to regulate cellular metabolism in response to CO2 availability in environments as diverse as the phagosome, yeast communities or liquid culture.

Highlights

Atmospheric carbon dioxide (CO2) with a concentration of 0.039% is central to the Earth’s biogeochemical carbon cycle but is sensed as a signal by many organisms
Oral and vaginal thrush, or bloodstream candidiasis are some of the diseases caused by the human pathogen Candida albicans
This molecule initiates the regulation of an essential protein: carbonic anhydrase, not through the known adenylyl cyclase CO2 sensor but as we discovered via a novel fungal CO2 sensing pathway involving the transcriptional regulator Rca1p

Summary

Introduction

Atmospheric carbon dioxide (CO2) with a concentration of 0.039% is central to the Earth’s biogeochemical carbon cycle but is sensed as a signal by many organisms. The nematode and parasite of insects Neoaplectana carpocapsae localizes its prey via a CO2 gradient [1], while avoidance behaviour in another nematode, Caenorhabditis elegans [2], or the model organism Drosophila melanogaster is provoked by elevated CO2 [3]. C. elegans detects CO2 via a cGMP-gated ion channel [2] whereas in D. melanogaster CO2 is sensed by a pair of 7 transmembrane domains chemoreceptors localized on specialized sensory neurons [4]. In the fungal kingdom CO2, under its hydrated form bicarbonate (HCO32), is critical for cellular metabolism. When cultured in a CO22enriched atmosphere, where sufficient HCO32 is spontaneously formed to meet the metabolic requirements, CAs are optional

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