Translational Regulation Promotes Oxidative Stress Resistance in the Human Fungal Pathogen Cryptococcus neoformans
| Autor: | Amanda L. M. Bloom, Christopher S. Campomizzi, John C. Panepinto, Jay Leipheimer, Yana Salei |
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| Rok vydání: | 2019 |
| Předmět: |
Transcription
Genetic RNA Stability Biology medicine.disease_cause Models Biological Microbiology Host-Microbe Biology 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Gene Expression Regulation Fungal transcription factors Virology Gene expression Translational regulation medicine Transcriptional regulation Humans Initiation factor transcriptional regulation mRNA stability Phosphorylation 030304 developmental biology Cryptococcus neoformans 0303 health sciences Kinase 030306 microbiology translational control Translation (biology) Cryptococcosis stress response biology.organism_classification Adaptation Physiological QR1-502 Cell biology Oxidative Stress Glucose Protein Biosynthesis mRNA degradation Reactive Oxygen Species Protein Processing Post-Translational 030217 neurology & neurosurgery Oxidative stress Research Article |
| Zdroj: | mBio mBio, Vol 10, Iss 6, p e02143-19 (2019) mBio, Vol 10, Iss 6 (2019) |
| ISSN: | 2150-7511 2161-2129 |
| DOI: | 10.1128/mbio.02143-19 |
| Popis: | Fungal survival in a mammalian host requires the coordinated expression and downregulation of a large cohort of genes in response to cellular stresses. Initial infection with C. neoformans occurs in the lungs, where it interacts with host macrophages. Surviving macrophage-derived cellular stresses, such as the production of reactive oxygen and nitrogen species, is believed to promote dissemination into the central nervous system. Therefore, investigating how an oxidative stress-resistant phenotype is brought about in C. neoformans not only furthers our understanding of fungal pathogenesis but also unveils mechanisms of stress-induced gene reprogramming. We discovered that H2O2-derived oxidative stress resulted in severe translational suppression and that this suppression was necessary for the accelerated decay and expression of tested transcripts. Cryptococcus neoformans is one of the few environmental fungi that can survive within a mammalian host and cause disease. Although many of the factors responsible for establishing virulence have been recognized, how they are expressed in response to certain host-derived cellular stresses is rarely addressed. Here, we characterize the temporal translational response of C. neoformans to oxidative stress. We find that translation is largely inhibited through the phosphorylation of the critical initiation factor eIF2α (α subunit of eukaryotic initiation factor 2) by a sole kinase. Preventing eIF2α-mediated translational suppression resulted in growth sensitivity to hydrogen peroxide (H2O2). Our work suggests that translational repression in response to H2O2 partly facilitates oxidative stress adaptation by accelerating the decay of abundant non-stress-related transcripts while facilitating the proper expression levels of select oxidative stress response factors. Our results illustrate translational suppression as a critical determinant of select mRNA decay, gene expression, and subsequent survival in response to oxidative stress. |
| Databáze: | OpenAIRE |
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