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Highly Reactive Group I Introns Ubiquitous in Pathogenic Fungi
Tianshuo Liu1, Anna Marie Pyle2
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
Abstract:
Systemic fungal infections are a growing public health threat, and yet viable antifungal drug targets are limited as fungi share a similar proteome with humans. However, features of RNA metabolism and the noncoding transcriptomes in fungi are distinctive. For example, fungi harbor highly structured RNA elements that humans lack, such as self-splicing introns within key housekeeping genes in the mitochondria. However, the location and function of these mitochondrial riboregulatory elements has largely eluded characterization. Here we used an RNA-structure-based bioinformatics pipeline to identify the group I introns interrupting key mitochondrial genes in medically relevant fungi, revealing their fixation within a handful of genetic hotspots and their ubiquitous presence across divergent phylogenies of fungi, including all highest priority pathogens such as Candida albicans, Candida auris, Aspergillus fumigatus and Cryptococcus neoformans. We then biochemically characterized two representative introns from C. albicans and C. auris, demonstrating their exceptionally efficient splicing catalysis relative to previously-characterized group I introns. Indeed, the C. albicans mitochondrial intron displays extremely rapid catalytic turnover, even at ambient temperatures and physiological magnesium ion concentrations. Our results unmask a significant new set of players in the RNA metabolism of pathogenic fungi, suggesting a promising new type of antifungal drug target.
Insights
Researchers identified unique fungal mitochondrial introns, revealing their potential as novel antifungal drug targets. These structured RNA elements are widespread in pathogenic fungi, offering new avenues for combating infections.
Area of Science:
- Mycology
- Molecular Biology
- RNA Biology
Background:
- Systemic fungal infections pose a significant public health challenge.
- Limited antifungal drug targets exist due to proteome similarity between fungi and humans.
- Fungal RNA metabolism and noncoding transcriptomes offer distinctive features for therapeutic intervention.
Purpose of the Study:
- To identify and characterize group I introns in the mitochondria of medically relevant fungi.
- To investigate the location, function, and phylogenetic distribution of these mitochondrial riboregulatory elements.
- To explore the potential of these fungal-specific RNA elements as novel antifungal drug targets.
Main Methods:
- Utilized an RNA-structure-based bioinformatics pipeline to identify group I introns.
- Analyzed the genetic hotspots and phylogenetic presence of introns in pathogenic fungi.
- Biochemically characterized the splicing efficiency of representative introns from Candida albicans and Candida auris.
Main Results:
- Identified group I introns within key mitochondrial genes across diverse fungal species, including major pathogens like Candida albicans, Candida auris, Aspergillus fumigatus, and Cryptococcus neoformans.
- Revealed that these introns are conserved within specific genetic hotspots and are ubiquitously present in divergent fungal phylogenies.
- Demonstrated exceptionally efficient splicing catalysis for characterized introns from C. albicans and C. auris, with rapid catalytic turnover under physiological conditions.
Conclusions:
- Uncovered a novel set of players in pathogenic fungal RNA metabolism.
- Mitochondrial group I introns represent a promising class of antifungal drug targets due to their unique fungal characteristics.
- Further research into these riboregulatory elements could lead to the development of new antifungal therapies.
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