Role of Ess1 in Growth, Morphogenetic Switching, and RNA Polymerase II Transcription in Candida albicans

Abstract

Candida albicans is a fungal pathogen that causes potentially fatal infections among immune-compromised individuals. The emergence of drug resistant C. albicans strains makes it important to identify new antifungal drug targets. Among potential targets are enzymes known as peptidyl-prolyl cis/trans isomerases (PPIases) that catalyze isomerization of peptide bonds preceding proline. We are investigating a PPIase called Ess1, which is conserved in all major human pathogenic fungi. Previously, we reported that C. albicans Ess1 is essential for growth and morphogenetic switching. In the present study, we re-evaluated these findings using more rigorous genetic analyses, including the use of additional CaESS1 mutant alleles, distinct marker genes, and the engineering of suitably-matched isogenic control strains. The results confirm that CaEss1 is essential for growth in C. albicans, but show that reduction of CaESS1 gene dosage by half (δ/+) does not interfere with morphogenetic switching. However, further reduction of CaEss1 levels using a conditional allele does reduce morphogenetic switching. We also examine the role of the linker α-helix that distinguishes C. albicans Ess1 from the human Pin1 enzyme, and present results of a genome-wide transcriptome analysis. The latter analysis indicates that CaEss1 has a conserved role in regulation of RNA polymerase II function, and is required for efficient termination of small nucleolar RNAs and repression of cryptic transcription in C. albicans.

The Ess1 prolyl isomerase: Traffic cop of the RNA polymerase II transcription cycle

“…Instead the elongated transcripts extended into neighboring genes or promoters, oriented in the same or opposite direction, often resulting in their increased or decreased expression [141–144]. Analogous results were observed for ess1 mutants in C. albicans using high-throughput RNA-seq analysis [145]. In summary, ess1 mutants show genomic chaos due to faulty mRNA and small non-coding RNA termination/3′-end formation and to high levels of cryptic transcription.…”

Antifungal Activity of N-(4-Halobenzyl)amides against Candida spp. and Molecular Modeling Studies

“…PPCTI2 belongs to the peptidyl prolyl cis-trans isomerases family of proteins, catalyzing the isomerization of the peptide bond preceding prolines within protein substrates [ 49 ]. Despite this family of proteins having not been fully characterized in Candida species, some of its members have been proposed as targets capable of overcoming drug resistance in C. albicans [ 50 , 51 ].…”

Cross-Talk of Phosphorylation and Prolyl Isomerization of the C-terminal Domain of RNA Polymerase II

“…Indeed, this termination pathway utilizes a distinct tripartite complex of Nrd1, Nab3, and Sen1 [ 178 ] where Nrd1-Nab3-Sen1 complex is recruited to the CTD via interaction between Nrd1 and phosphoryl Ser5 [ 169 ]. Recently it was shown that Candida albicans Ess1 is necessary for efficient termination of snoRNAs [ 179 ] and it was also shown that the prolyl isomerase activity of Ess1 is required for Nrd1-dependent transcription termination of small ncRNAs [ 43 ]. Ess1 also promotes the release of Nrd1 from CTD in terminator regions [ 43 ].…”