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（由申请人提供）：赖氨酸的囊性是蛋白质的最突出的翻译后修饰（PTM），并且已被认为在我们对染色质功能的基因修饰和调节基因的调节中起关键作用。赖氨酸乙酰基transe虫（KDAC）在最后几十年中的生理过程中的细胞过程和从癌症到感染的过程仍然存在。致病性的念珠菌在很大程度上没有探索的念珠菌。 Thate蛋白在控制白色念珠菌的细胞生理学和基于我们的前期的细胞生理学中发挥着关键作用。在DNA损伤中，形态发生，生物膜形成，抗真菌药物的耐药性和病毒性酶的含量涉及LIG4的lig4。 NHEJ） - exepentepent的DNA修复和调节白色念珠菌的形态发生和NCE。因此，我们的联合应用是iDharacteriz的，c.albicans hat1的组蛋白和非固定剂靶基因，并研究其在调节线粒体功能中的不确定作用以及在NHEJ DNA修复中的可能作用假设并通过追求以下三个特定AM来实现应用的目标：1）在调节白色念珠菌毒力的情况下，识别和表征HAT1的组蛋白和组蛋白（非染色质） HAT1在NCRNA的处理中的作用。

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

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

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

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