Stress Responsive Reprogramming of Translating mRNA Pools in C. neoformans

摘要： 新型隐球菌是HIV感染和移植的主要合并症，死亡率高 由于现有抗真菌药物的毒性和有限的可用性和有效性，作为环境 然而，隐球菌的发病机制需要适应人类宿主的环境。我们的工作 使我们得出了一个科学前提，即C. neoformans需要两个连续的后- 转录事件。首先，加速降解的mRNA编码代谢昂贵的过程， 如翻译机制，第二，应激反应mRNA的翻译通过帽- 独立的翻译机制。这个前提暗示核糖体是一个传感器 通过翻译质量控制机制来控制细胞压力。本提案的目的是调查共同- 翻译质量控制作为温度胁迫下mRNA加速降解的触发因素 （目标1），并将探讨帽独立的翻译机制（目标2）在压力适应。目标2将 重点关注在C.我们假设他们通过 内部核糖体进入位点（IRES）响应温度和氧化应激。最后，我们将评估 核糖体相关的质量控制在饥饿应激反应翻译中的作用， 定义每个质量控制路径在C响应中的贡献。新型化合物 压力源（目标3）。这些研究将是第一次对C语言中的翻译进行研究。新形式，包括 核糖体分析在这种病原体中的首次应用翻译被认为是可重定向的 但真核生物的保护被认为是一个障碍。只有通过对翻译的分子研究 调控可以将该过程的真菌特异性方面鉴定为药物靶点，用于未来的研究。

Abstract: Cryptococcus neoformans is a major comorbidity of HIV infection and transplantation with high mortality rates due to the toxicity and limited availability and efficacy of existing antifungal agents. As an environmental saprophyte, cryptococcal pathogenesis requires adaptation to the environment of the human host. Our work has led us to the scientific premise that stress adaptation in C. neoformans requires two sequential post- transcriptional events. First, the accelerated degradation mRNAs encoding metabolically expensive processes such as the translational machinery, and second, the translation of stress response mRNAs via cap- independent translation mechanisms on recycled ribosomes. This premise implicates the ribosome as a sensor of cellular stress through translation quality control mechanisms. The aims in this proposal will investigate co- translational quality control as a trigger for accelerated mRNA degradation in response to temperature sturess (Aim1) and will investigate cap-independent translation mechanisms (Aims 2) in stress adaptation. Aim 2 will focus on two CNBP orthologues expressed in C. neoformans that we hypothesize to regulate translation via internal ribosome entry sites (IRES) in response to temperature and oxidative stress. Finally, we will assess the contributing role of ribosome-associated quality control in starvation stress responsive translation and define the contributions of each quality control pathway in the response of C. neoformans to compound stressors (Aim 3). These studies will be the first investigation of translation in C. neoformans, and include the first application of ribosome profiling in this pathogen. Translation is known to be pharmacologically targetable but conservation in eukaryotes is thought to be a hindrance. Only through molecular investigation of translation regulation can fungal-specific aspects of the process be identified for future investigation as drug targets.