Stress Responsive Reprogramming of Translating mRNA Pools in C. neoformans

摘要： 新生隐球菌是HIV感染和移植的主要共病，死亡率高。 由于现有抗真菌药物的毒性和可获得性和有效性有限，导致了死亡率。作为一种环境保护 腐生、隐球菌的致病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，即新生葡萄球菌的应激适应需要两个连续的后 转录事件。首先，编码代谢代价高昂的过程的加速降解的mRNAs 如翻译机制，第二，应激反应mRNAs的翻译通过帽- 循环核糖体上的独立翻译机制。这一前提意味着核糖体是一种传感器。 通过翻译质量控制机制控制细胞压力。这份提案中的目标将调查联合 翻译质量控制是温度胁迫引起的mRNA加速降解的触发因素 (Aim1)，并将研究压力适应中的帽非依赖性翻译机制(AIMS 2)。目标2将 关注两个在新生葡萄球菌中表达的CNBP同源基因，我们假设它们是通过 内部核糖体进入位点(IRES)对温度和氧化应激的反应。最后，我们将评估 核糖体相关质量控制在饥饿应激反应翻译和转录中的作用 确定每条质量控制途径在新生葡萄球菌对化合物的反应中的作用 应激源(目标3)。这些研究将是对新生葡萄球菌翻译的第一次调查，包括 核糖体图谱在该病中的首次应用。众所周知，翻译在药物上是有靶向性的 但真核生物的保护被认为是一种障碍。只有通过翻译的分子研究 监管可以将该过程中真菌特有的方面确定为未来的药物靶点。

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.