Abstract
A forward genetic screening approach identified orf19.2500 as a gene controlling Candida albicans biofilm dispersal and biofilm detachment. Three-dimensional (3D) protein modeling and bioinformatics revealed that orf19.2500 is a conserved mitochondrial protein, structurally similar to, but functionally diverged from, the squalene/phytoene synthases family. The C. albicans orf19.2500 is distinguished by 3 evolutionarily acquired stretches of amino acid inserts, absent from all other eukaryotes except a small number of ascomycete fungi. Biochemical assays showed that orf19.2500 is required for the assembly and activity of the NADH ubiquinone oxidoreductase Complex I (CI) of the respiratory electron transport chain (ETC) and was thereby named NDU1. NDU1 is essential for respiration and growth on alternative carbon sources, important for immune evasion, required for virulence in a mouse model of hematogenously disseminated candidiasis, and for potentiating resistance to antifungal drugs. Our study is the first report on a protein that sets the Candida-like fungi phylogenetically apart from all other eukaryotes, based solely on evolutionary “gain” of new amino acid inserts that are also the functional hub of the protein.
Highlights
Candida albicans biofilms are dynamic communities in which transitions between planktonic and sessile modes of growth occur interchangeably in response to different environmental cues
Our analyses showed that the C. albicans mitochondrial protein NDU1 has structures distinct to CTG clade proteins, and these inserts may be functionally important for enzymatic activity or protein–protein interactions, distinct for Candida spp
Bioinformatic, and biochemical approaches to identify NDU1, a gene that encodes a mitochondrial protein that is evolutionarily divergent from other eukaryotic orthologues
Summary
Candida albicans biofilms are dynamic communities in which transitions between planktonic and sessile modes of growth occur interchangeably in response to different environmental cues. Biofilms growing on mucosal tissues or indwelling medical devices serve as localized reservoirs of highly drug resistant cells. Cells that disperse from this nidus into the systemic environment cause biofilm-associated disseminated infections [1,2]. Our previous reports have shown that biofilm-dispersed cells are predominantly lateral yeast cells released from the hyphal layers of the biofilm [3]. Biofilm-dispersed yeast cells have considerably better adherence to, and invasion of human tissues when compared to planktonic cells, and thereby are significantly more virulent than their free-living counterparts [3,4]. Global transcriptomic analysis of dispersed cells corroborated the virulence attributes, revealing
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