Identification of genomewide alternative splicing events in sequential, isogenic clinical isolates of Candida albicans reveals a novel mechanism of drug resistance and tolerance to cellular stresses

Suraya Muzafar, Ravi Datta Sharma, Abdul Haseeb Shah, Naseem A. Gaur, Ujjaini Dasgupta, Neeraj Chauhan, Rajendra Prasada

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Alternative splicing (AS)-a process by which a single gene gives rise to different protein isoforms in eukaryotes-has been implicated in many basic cellular processes, but little is known about its role in drug resistance and fungal pathogenesis. The most common human fungal pathogen, Candida albicans, has introns in 4 to 6% of its genes, the functions of which remain largely unknown. Here, we report AS regulating drug resistance in C. albicans. Comparative RNA-sequencing of two different sets of sequential, isogenic azole-sensitive and-resistant isolates of C. albicans revealed differential expression of splice isoforms of 14 genes. One of these was the superoxide dismutase gene SOD3, which contains a single intron. The sod3Δ/Δ mutant was susceptible to the antifungals amphotericin B (AMB) and menadione (MND). While AMB susceptibility was rescued by overexpression of both the spliced and unspliced SOD3 isoforms, only the spliced isoform could overcome MND susceptibility, demonstrating the functional relevance of this splicing in developing drug resistance. Furthermore, unlike AMB, MND inhibits SOD3 splicing and acts as a splicing inhibitor. Consistent with these observations, MND exposure resulted in increased levels of unspliced SOD3 isoform that are unable to scavenge reactive oxygen species (ROS), resulting in increased drug susceptibility. Collectively, these observations suggest that AS is a novel mechanism for stress adaptation and overcoming drug susceptibility in C. albicans.

Original languageEnglish (US)
Article numbere00608
JournalmSphere
Volume5
Issue number4
DOIs
StatePublished - 2020

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Keywords

  • Alternative splicing
  • Amphotericin B
  • Candida albicans
  • Menadione
  • SOD3

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