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T3SS Effector Regulation of Bacterial Metabolism

T3SS 细菌代谢的效应器调节

基本信息

批准号：
10425770
负责人：
Philip Ross Hardwidge
金额：
$ 18.65万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-22 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425770
关键词：
Affect Area Arginine Bacterial Physiology Bacterial Proteins Behavior Biochemical Biological Assay Cells Citrobacter rodentium Cyclic AMP Receptor Protein DNA DNA Binding DNA Damage Data Electrophoretic Mobility Shift Assay Enterocytes Enzymes Escherichia coli Escherichia coli EHEC Family Funding Mechanisms Future Gene Expression Gene Expression Regulation Genes Glucosamine Glutathione Goals Gram-Negative Bacteria Inflammatory Innate Immune System Investigation Mammalian Cell Manuscripts Mass Spectrum Analysis Measurement Mediating Metabolism Molecular Conformation NF-kappa B Names Orthologous Gene Oxidative Stress Pathogenicity Island Pathway interactions Play Post-Translational Protein Processing Production Protein Glycosylation Proteins Publishing Pyruvaldehyde Regulation Regulon Reporter Repressor Proteins Research Role Salmonella Salmonella enterica Stress Structure Surface Plasmon Resonance System Testing Type III Secretion System Pathway Virulence Work bacterial metabolism base complex biological systems experimental study glutathione synthase glycosylation glycosyltransferase improved innovation insight novel pathogenic bacteria transcription factor transcriptome transcriptome sequencing uptake

项目摘要

Project Summary. Many Gram-negative bacterial pathogens interact with mammalian cells by using secretion systems to inject virulence proteins directly into infected host cells. Some of these injected protein ‘effectors’ are enzymes that modify the structure and inhibit the function of mammalian proteins by catalyzing the addition of unusual post- translational modifications. Type III secretion system (T3SS) effectors play essential roles in virulence and their mechanisms have provided great insight into the functions and components of the innate immune system. T3SS effectors are believed to be inactive until they are injected into host cells, where they then fold into their active conformations. However, recent work with the NleB and SseK glycosyltransferases from E. coli, Citrobacter rodentium, and Salmonella enterica has challenged that dogma. NleB glycosylates and activates the bacterial glutathione synthetase (GshB) enzyme, resulting in enhanced glutathione production and improved C. rodentium survival in oxidative stress conditions. SseK1 is active within Salmonella enterica, where it glycosylates and enhances the activity of several enzymes that are critical to the ability of Salmonella to resist methylglyoxal stress. In support of long-term goals to identify and understand the functional significance of bacterial protein glycosylation by NleB and SseK1, two new bacterial targets of SseK1, namely NagC and CRP have been discovered. NagC is a dual activator-repressor that controls GlcNAc uptake and metabolism. NagC also regulates locus of enterocyte effacement (LEE) gene expression in enterohemorrhagic E. coli (EHEC). The LEE is an important pathogenicity island that encodes the T3SS and many effector proteins. The catabolite repressor protein [(CRP); also referred to as the catabolite activator protein (CAP)], is a global regulator that mediates the expression of ~150 genes, including those important to GlcNAc metabolism and several T3SS components in Salmonella. The central hypothesis to be tested is that Arg-glycosylation of NagC and CRP by SseK1 affects Salmonella virulence gene regulation and metabolism. The specific aims are: 1) Quantify the extent to which Arg-glycosylation of NagC and CRP affects the ability of these transcription factors to bind DNA; 2) Characterize the impact of Arg-glycosylation of NagC and CRP on the Salmonella transcriptome. The proposed work is highly suitable for the R21 funding mechanism because of the innovation of the research premise and novel hypothesis to be tested. Such data will establish the framework for future investigation of the mechanistic aspects and functional significance of T3SS effector regulation of bacterial transcription factors.

项目总结。