Stress Responsive Reprogramming of Translating mRNA Pools in C. neoformans

新型隐球菌中翻译 mRNA 库的应激反应性重编程

• 批准号: 10088140
• 负责人: John C Panepinto
• 金额: $ 6.41万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-10 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088140
• 关键词: 5' Untranslated Regions; Antifungal Agents; Antifungal Therapy; Area; Biology; Carbon; Cellular Stress; Cryptococcus; Cryptococcus neoformans; Drug Targeting; Elements; Environment; Eukaryota; Event; Exposure to; Future; Genetic Transcription; Goals; HIV; HIV Infections; Human; Internal Ribosome Entry Site; Investigation; Mammals; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Molecular; Molecular Chaperones; Monitor; N-terminal; Nutrient; Oxidative Stress; Pathogenesis; Pathway interactions; Peptides; Pharmacology; Process; Protein Biosynthesis; Proteins; Quality Control; RNA; Reactive Oxygen Species; Regulation; Repression; Resources; Ribosomal Proteins; Ribosomes; Role; Specificity; Starvation; Stress; Temperature; Testing; Time; Toxic effect; Translating; Translations; Transplantation; Virulence; Work; Yeasts; Zinc; antimicrobial; biological adaptation to stress; comorbidity; defined contribution; drug development; lens; mRNA Decay; mRNA Transcript Degradation; microorganism; mortality; novel; pathogen; polypeptide; response; ribosome profiling; sensor; stressor

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.

抽象的： 新型隐球菌是HIV感染和移植的主要合并症，死亡率高 由于现有抗真菌剂的毒性以及有限的可用性和功效。作为一个环保 腐生菌、隐球菌的发病机制需要适应人类宿主的环境。我们的工作 使我们得出了这样的科学前提：新型隐球菌的应激适应需要两个连续的后适应过程。 转录事件。首先，编码代谢昂贵过程的 mRNA 加速降解 例如翻译机制，第二，应激反应 mRNA 通过帽的翻译 回收核糖体的独立翻译机制。这个前提暗示核糖体作为传感器 通过翻译质量控制机制来控制细胞应激。该提案的目的是调查共同 翻译质量控制作为响应温度应激加速 mRNA 降解的触发因素 （目标 1）并将研究压力适应中与上限无关的翻译机制（目标 2）。目标2将 重点关注在 C. neoformans 中表达的两个 CNBP 直向同源物，我们假设它们通过 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 核糖体相关质量控制在饥饿应激反应翻译中的贡献作用 定义每个质量控制途径在新型隐球菌对化合物的反应中的贡献 压力源（目标 3）。这些研究将是对 C. neoformans 翻译的首次调查，包括 核糖体分析在该病原体中的首次应用。已知翻译具有药理学靶向性 但真核生物的保护被认为是一个障碍。仅通过翻译的分子研究 监管可以确定该过程的真菌特定方面，以供未来研究作为药物靶标。