Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen whose pathogenic lifestyle is linked to its ability to cope with fluctuating levels of copper (Cu), an essential metal involved in multiple virulence mechanisms, within distinct host niches. During lethal cryptococcal meningitis in the brain, C. neoformans senses a Cu-deficient environment and is highly dependent on its ability to scavenge trace levels of Cu from its host and adapt to Cu scarcity to successfully colonize this niche. In this study, we demonstrate for this critical adaptation, the Cu-sensing transcription factor Cuf1 differentially regulates the expression of the SOD1 and SOD2 superoxide dismutases in novel ways. Genetic and transcriptional analysis reveals Cuf1 specifies 5’-truncations of the SOD1 and SOD2 mRNAs through specific binding to Cu responsive elements within their respective promoter regions. This results in Cuf1-dependent repression of the highly abundant SOD1 and simultaneously induces expression of two isoforms of SOD2, the canonical mitochondrial targeted isoform and a novel alternative cytosolic isoform, from a single alternative transcript produced specifically under Cu limitation. The generation of cytosolic Sod2 during Cu limitation is required to maintain cellular antioxidant defense against superoxide stress both in vitro and in vivo. Further, decoupling Cuf1 regulation of Sod2 localization compromises the ability of C. neoformans to colonize organs in murine models of cryptococcosis. Our results provide a link between transcription factor–mediated alteration of protein localization and cell proliferation under stress, which could impact tissue colonization by a fungal pathogen.
Highlights
It is yet to be determined whether decreases in local Cu concentrations are because of inherent low bioavailability of Cu within these host niches or if bona fide Cu nutritional immunity mechanisms are implemented in response to infection, similar to those described for Fe, Mn, and Zn
A strong enrichment of Cuf1 was observed within the SOD2 promoter with a 6-fold induction in transcript levels when cells were grown under Cu limitation (Fig. 1, C and D)
Under Cu-limiting growth conditions, Cuf1 activates the transcription of genes such as those involved in Cu+ import, and other functions, that allow cells to adapt to low levels of this essential trace element [25, 42, 43]
Summary
Sarela Garcia-Santamarina , Martina Ralle , David R. Thiele1,3,4,* From the 1Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA; 2Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA; 3Department of Biochemistry, 4Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA
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