Transcription factor–driven alternative localization of Cryptococcus neoformans superoxide dismutase
| Autor: | Sarela García-Santamarina, David R. Loiselle, Dennis J. Thiele, Aaron D. Smith, Martina Ralle, Timothy A.J. Haystead |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Biochemistry Mice Superoxide Dismutase-1 5’-UTR 5’-untranslated region Protein Isoforms mRNA-sequencing MIP mitochondrial import peptide transcription factor Cu copper chemistry.chemical_classification Regulation of gene expression IMS intermembrane space biology ChIP-sequencing subcellular fractionation Cell biology 5’-RACE 5’-rapid amplification of cDNA ends BCS bathocuproinedisulfonic acid CTR copper transporter Female Subcellular Fractions Research Article CuRE copper responsive element Gene isoform SOD1 SOD2 ICP-MS inductively coupled plasma mass spectrometry Fungal Proteins Superoxide dismutase 03 medical and health sciences ROS reactive oxygen species SC synthetic complete SOD superoxide dismutase Animals Molecular Biology Transcription factor Cryptococcus neoformans posttranslational modification Reactive oxygen species 030102 biochemistry & molecular biology Superoxide Dismutase Cell Biology MT metallothionein biology.organism_classification infection CFU colony forming unit AOX alternative oxidase Disease Models Animal 030104 developmental biology chemistry copper biology.protein gene regulation NAT N-acetyltransferase Transcription Factors HA hemagglutinin |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.100391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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