Poster abstracts
Poster number 118 submitted by Corey Knowles
Stress-induced translational control induces the ISR in the human pathogen Cryptococcus neoformans
Corey M. Knowles (Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA), David Goich (Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA), Gemma E. May (Department Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA), Joel McManus (Department Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA), John C. Panepinto (Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA)
Abstract:
Cryptococcus neoformans is a ubiquitous environmental fungus and opportunistic human pathogen, primarily impacting immunocompromised hosts such as those living with HIV/AIDS. One of C. neoformans’ key virulence traits is its ability to rapidly adapt to the harsh environment inside the human lung. Here, it is subject to both a sudden temperature shift to 37°C and oxidative stress from resident lung macrophages, among other stressors. Exposure to these stressors is met with, and combated by, an initial repression of translation and induction of the integrated stress response (ISR), resulting in a reprogrammed stress-responsive translatome. To better understand the mechanisms involved in the translational response to host stress, we’ve begun to characterize the C. neoformans response to these stressors in culture. We find oxidative stress causes robust eIF2α phosphorylation, Gcn2-dependent polysome collapse, and mild decay of ribosomal protein (RP) mRNAs. Conversely, temperature stress is met with robust RP mRNA decay and only moderate eIF2α phosphorylation, yet leads to similar polysome collapse that is Gcn2-independent. Interestingly, ribosome collisions, as visualized by disome profiling, are induced in response to temperature stress, while no increase in disomes is seen in response to oxidative stress. This difference was unexpected given recent work linking ribosome collisions to eIF2&alpha phosphorylation. Although the amount of eIF2α phosphorylation varies in response to each stressor, translational activation of C. neoformans Gcn4 is comparable, suggesting similar induction of the ISR. Despite comparable production of Gcn4 protein, the magnitude of ISR target mRNA induction varies with the type and intensity of the stressor. Future work will seek to identify mRNAs whose translation changes in response to these stresses and evaluate mRNA features that specify their fates.
Keywords: translation regulation, stress response