The Candida albicans acetylome in fungal virulence

真菌毒力中的白色念珠菌乙酰化组

基本信息

批准号：
9750616
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-17 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750616
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 Genes 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 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 genetic approach genome-wide histone modification human disease insight member mitochondrial metabolism non-histone protein novel pathogenic fungus protein function public health relevance reverse genetics transcriptome sequencing

项目摘要

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（由应用程序提供）：赖氨酸乙酰化是蛋白质的最突出的翻译后修饰（PTM）之一，并被认为通过组蛋白修饰和调节染色质功能在调节基因表达中起关键作用。尽管在过去几十年中，我们对赖氨酸乙酰基转移酶（KAT）和赖氨酸脱乙酰基酶（KDAC）的理解取得了令人印象深刻的进步，但可逆赖氨酸乙酰化在癌症和病理学中的基本细胞过程中可逆赖氨酸乙酰化在癌症到感染性疾病中的作用仍然很少。特别是，单个Kats/KDACS成员的染色质和非染色质功能的解剖仍然代表了一个重大的科学挑战。例如，有令人信服的证据表明，病原真菌（例如白色念珠菌）的蛋白质调节病毒的赖氨酸乙酰化，但基本机制在很大程度上尚不清楚。理解这些机制更为重要，因为白色念珠菌乙酰转移酶Kats的识别基序是真菌王国独有的，因此代表了抗真菌药物发现的承诺靶标。拟议研究的中心假设是蛋白乙酰化在控制白色念珠菌的细胞生理学和病毒中起着关键作用。我们根据初步数据提出了这一假设，表明赖氨酸乙酰化是白色念珠菌中PTM的丰富形式。此外，我们以前的工作已经实施了白色念珠菌HAT1，一种典范的组蛋白赖氨酸乙酰酶，在DNA损伤修复，形态发生，生物膜形成，抗真菌耐药性和病毒中。但是，该生物体中其他几种赖氨酸乙酰转移酶的作用尚不清楚。我们的初步研究还对Lig4的两个特定赖氨酸残基（K654和K655）进行了适应，这是一种参与非同源末端连接（NHEJ）的重要蛋白质（NHEJ）依赖性的DNA修复，并调节C. albicans的形态发生和病毒。此外，新的初步RNA-seq数据表明，HAT1在线粒体功能以及非编码RNA（NCRNA）的处理和调节中具有重要作用。因此，我们联合应用中的主要目标是识别和表征白色念珠菌HAT1的组蛋白和非固定靶基因，并研究其在调节线粒体功能调节中的不确定作用，并在NHEJ DNA修复中起作用。在初步数据的指导下，我们希望通过追求以下三个特定目的来检验我们的中心假设，并实现本应用程序的目标：1）识别和表征HAT1的组蛋白和非histone和非固定蛋白（非染色质）目标。 2）研究NHEJ DNA修复途径在白色念珠菌病毒调节中的乙酰化可能作用。 3）研究HAT1在NCRNA处理中的作用。预计该提案的回报将是重要的，因为我们期望发现对白色念珠菌发病机理重要的关键细胞过程调节的新型调节方式。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcriptome Signatures Predict Phenotypic Variations of Candida auris.

DOI：
10.3389/fcimb.2021.662563
发表时间：
2021
期刊：
Frontiers in cellular and infection microbiology
影响因子：
5.7
作者：
Jenull S;Tscherner M;Kashko N;Shivarathri R;Stoiber A;Chauhan M;Petryshyn A;Chauhan N;Kuchler K
通讯作者：
Kuchler K

Identification of Genomewide Alternative Splicing Events in Sequential, Isogenic Clinical Isolates of Candida albicans Reveals a Novel Mechanism of Drug Resistance and Tolerance to Cellular Stresses.

白色念珠菌序列同基因临床分离株中全基因组选择性剪接事件的鉴定揭示了细胞应激耐药性和耐受性的新机制。

DOI：
10.1128/msphere.00608-20
发表时间：
2020
期刊：
mSphere
影响因子：
4.8
作者：
Muzafar,Suraya;Sharma,RaviDatta;Shah,AbdulHaseeb;Gaur,NaseemA;Dasgupta,Ujjaini;Chauhan,Neeraj;Prasad,Rajendra
通讯作者：
Prasad,Rajendra

The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of Candida auris.

DOI：
10.1128/msphere.00973-20
发表时间：
2020-10-14
期刊：
mSphere
影响因子：
4.8
作者：
Shivarathri R;Jenull S;Stoiber A;Chauhan M;Mazumdar R;Singh A;Nogueira F;Kuchler K;Chowdhary A;Chauhan N
通讯作者：
Chauhan N

Transcriptomics and Phenotyping Define Genetic Signatures Associated with Echinocandin Resistance in Candida auris.