The Candida albicans acetylome in fungal virulence

真菌毒力中的白色念珠菌乙酰化组

• 批准号: 9333188
• 负责人: NEERAJ CHAUHAN
• 金额: $ 39.75万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-17 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333188
• 关键词: Acetylation; Acetylesterase; Acetyltransferase; Affect; Antifungal Agents; Bioinformatics; Biology; Candida; Candida albicans; Candidiasis; Cell physiology; Chromatin; Communicable Diseases; DNA Repair; DNA Repair Pathway; Data; Deacetylase; Defect; Dissection; Enzymes; Eukaryota; Filament; Foundations; Fungal Drug Resistance; Gene Expression Regulation; Gene Targeting; HAT1 gene; Histone Acetylation; Histones; Human; Individual; Joints; Knowledge; Left; Lysine; Malignant Neoplasms; Mediating; Microbial Biofilms; Mission; Mitochondria; Modification; Molecular; Molecular Genetics; Morphogenesis; Mutation Analysis; Nonhomologous DNA End Joining; Organism; Outcome; Oxidative Stress; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Physiology; Play; Positioning Attribute; Post-Translational Protein Processing; Protein Acetylation; Proteins; Proteomics; Public Health; Publications; RNA Processing; Regulation; Research; Role; Testing; Therapeutic; United States National Institutes of Health; Untranslated RNA; Virulence; Work; base; cell growth; drug discovery; fungus; genetic approach; genome-wide; histone modification; human disease; insight; member; mitochondrial metabolism; non-histone protein; novel; protein function; public health relevance; reverse genetics; transcriptome sequencing

 DESCRIPTION (provided by applicant): Lysine acetylation is one of the most prominent post-translational modifications (PTM) of proteins and has been recognized to play a key role in regulation of gene expression by histone modification and modulation of chromatin function. Despite impressive advances in our understanding of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) during the last decades, the role of reversible lysine acetylation in fundamental cellular processes in physiology and pathology from cancer to infectious diseases still remains poorly understood. In particular, the dissection of chromatin and non-chromatin functions of individual KATs/KDACs members still represents a major scientific challenge. For example, there is compelling evidence that lysine acetylation of proteins modulates virulence of pathogenic fungi such as Candida albicans, but the underlying mechanisms have remained largely unexplored. Understanding these mechanisms is all the more important because the recognition motifs of C. albicans acetyltransferases KATs are unique to the fungal kingdom and thus represent promising targets for antifungal drug discovery. The central hypothesis of the proposed research is that protein acetylation plays pivotal roles in controlling the cellular physiology and virulence of C. albicans. We formulated this hypothesis based on our preliminary data indicating that lysine acetylation is an abundant form of PTM in C. albicans. Furthermore, our previous work has implicated C. albicans Hat1, a paradigmatic histone lysine acetylase, in DNA damage repair, morphogenesis, biofilm formation, antifungal drug resistance, and virulence. However, the roles of several other lysine acetyltransferase enzymes in this organism have remained unknown. Our preliminary studies have also implicated acetylation at two specific lysine residues (K654 and K655) of Lig4, an important protein involved in Non-Homologous End Joining (NHEJ)-dependent DNA repair and modulating morphogenesis and virulence of C. albicans. Furthermore, new preliminary RNA-seq data suggest that Hat1 has important roles in mitochondrial function, as well as in the processing and regulation of non-coding RNAs (ncRNA). The main objective in our joint application is therefore to identify and characterize the histone and non-histone target genes of C. albicans Hat1 and to investigate its ill-defined role in regulation of mitochondrial function and a possible role in the NHEJ DNA repair. Guided by the preliminary data, we expect to test our central hypothesis and to accomplish the objectives of this application by pursuing the following three Specific Aims: 1) To identify and characterize both histone and non- histone (non-chromatin) targets of Hat1. 2) To investigate the possible role of acetylation of the NHEJ DNA repair pathway in regulation of C. albicans virulence. 3) To investigate role of Hat1 in the processing of ncRNA. The payoffs of this proposal are expected to be significant because we expect to uncover novel modes of regulation of key cellular processes important for pathogenesis of C. albicans.

 描述（由申请人提供）：赖氨酸乙酰化是蛋白质最重要的翻译后修饰（PTM）之一，并且已被认为在通过组蛋白修饰和染色质功能调节基因表达中起关键作用。尽管在过去的几十年里，我们对赖氨酸乙酰转移酶（KAT）和赖氨酸脱乙酰酶（KDAC）的理解取得了令人印象深刻的进展，但可逆的赖氨酸乙酰化在从癌症到感染性疾病的生理学和病理学的基本细胞过程中的作用仍然知之甚少。特别是，单个KAT/KDAC成员的染色质和非染色质功能的解剖仍然是一个重大的科学挑战。例如，有令人信服的证据表明，赖氨酸乙酰化的蛋白质调节致病真菌，如白色念珠菌的毒力，但潜在的机制仍然在很大程度上未被探索。由于C.白色念珠菌乙酰转移酶KAT是真菌界所特有的，因此代表了发现抗真菌药物的有希望的靶点。该研究的中心假设是蛋白质乙酰化在控制C.白色念珠菌我们根据我们的初步数据阐明了这一假设，表明赖氨酸乙酰化是C.白色念珠菌此外，我们以前的工作涉及C。白色念珠菌Hat 1是一种典型的组蛋白赖氨酸乙酰化酶，在DNA损伤修复、形态发生、生物膜形成、抗真菌药物耐药性和毒力中起重要作用。然而，其他几种赖氨酸乙酰转移酶在这种生物体中的作用仍然未知。我们的初步研究还表明Lig 4的两个特异性赖氨酸残基（K654和K655）发生乙酰化，Lig 4是一种重要的蛋白质，参与非同源末端连接（NHEJ）依赖的DNA修复并调节C.白色念珠菌此外，新的初步RNA-seq数据表明，Hat 1在线粒体功能以及非编码RNA（ncRNA）的加工和调节中发挥重要作用。因此，我们联合申请的主要目的是鉴定和表征C. albicans Hat 1的表达，并研究其在线粒体功能调节中的不明确作用以及在NHEJ DNA修复中的可能作用。在初步数据的指导下，我们期望通过追求以下三个具体目标来测试我们的中心假设并实现本申请的目标：1）鉴定和表征Hat 1的组蛋白和非组蛋白（非染色质）靶标。2)探讨NHEJ DNA修复途径的乙酰化在C.白色念珠菌毒力3)探讨Hat 1在ncRNA加工中的作用。这项建议的回报预计将是显着的，因为我们希望发现新的模式，调节的关键细胞过程的重要性，发病机制的C。白色念珠菌