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Ehrlichia Notch SLiM-activated oncoprotein inhibition of apoptosis

埃里希氏菌Notch SLiM激活的癌蛋白抑制细胞凋亡

基本信息

批准号：
10513824
负责人：
JERE W MCBRIDE
金额：
$ 40万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-01 至 2026-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10513824
关键词：
Apoptosis Apoptosis Inhibitor Apoptotic BCL-2 Protein BIR Domain Bacteria Binding CASP3 gene Caspase Cell Communication Cell Survival Cell physiology Cells Development Disease Down-Regulation Ehrlichia Ehrlichia chaffeensis Ehrlichiosis Etiology Eukaryotic Cell Event FBXW7 gene Genetic Transcription Genome Goals Host Defense Host Defense Mechanism Human Immune Immune Evasion Infection Inflammation Inhibition of Apoptosis Investigation Knowledge Laboratories Life Ligands Link MCL1 gene Mediating Membrane Proteins Mitochondria Molecular Molecular Mimicry Mononuclear Notch Signaling Pathway Oncoproteins Pathway interactions Phagocytes Play Positioning Attribute Post-Translational Protein Processing Protein Inhibition Proteins Receptor Signaling Regulation Research Role Science Signal Pathway Signal Transduction Surface System TLR2 gene Tandem Repeat Sequences Toll-like receptors in vivo mimetics mimicry new therapeutic target notch protein novel therapeutic intervention pathogen prevent programs protein protein interaction receptor receptor binding receptor expression tick-borne ubiquitin ligase

项目摘要

ABSTRACT Ehrlichia chaffeensis (E. ch.) is a gram-negative, obligately intracellular bacterium and the etiologic agent of human monocytotropic ehrlichiosis (HME), an emerging, life-threatening, tick-borne zoonosis. E. ch. preferentially infects mononuclear phagocytes and survives intracellularly by subverting innate immune defenses mediated in part by tandem repeat protein (TRP) effectors. Within the last decade, our laboratory has identified a multitude of molecular ehrlichial TRP-host interactions, many that are new to science, illuminating the breath and complexity of pathogen-host interaction dynamics that occur during infection. We have shown that E. ch. is dependent on activation of conserved eukaryotic signaling pathways including Notch and Wnt for infection. However, understanding the molecular basis of Notch activation events, whereby E. ch. repurposes Notch signaling for infection remains a major gap in our knowledge. Thus, the purpose of this investigation is to define the molecular and cellular mechanisms E. ch. has evolved to repurpose Notch signaling for infection. We propose that E. ch. TRP120 has distinct eukaryotic protein interaction modules known as short linear motifs (SLiMs) that mimic Notch ligand function and directly engage cognate receptors to exploit Notch signaling for infection. This investigation will address our limited understanding of the functionally diverse roles of protein interaction modules in the continuum of host-pathogen interactions and cellular reprogramming. The long-term goal of this research is to define the molecular basis of Ehrlichia host cell mimicry, and the mechanisms involved in infection and immune evasion. The objective of this proposal is to determine the molecular interactions involved and functional mechanisms whereby E. ch. TRP120 Notch ligand mimicry establishes and promotes infection by inhibiting host cell apoptosis. We hypothesize that E. ch. TRP120 has a Notch SLiM mimetic that activates Notch signaling to upregulate anti-apoptotic regulators (MCL1 and NICD), thereby inhibiting mitochondrial apoptotic signaling and caspase activation. Aim 1 will define the E. ch. TRP120 Notch SLiM mimetic and investigate receptor binding and signaling; Aim 2 will examine E. ch. TRP120 Notch-upregulated MCL1 inhibition of mitochondrial apoptosis; and Aim 3 will investigate the role of E. ch. Notch stabilization of XIAP and inhibition of caspase activation. This investigation will extend our knowledge of the molecular interactions by which E. ch. TRP120 surface protein exploits Notch signaling to inhibit apoptosis and promote host cell survival and infection. The significance of this research is defining the mechanistic strategies whereby intracellular pathogens with small genomes and a limited number of effector proteins, have evolved host mimicry modules to repurpose host cell signaling to manipulate downstream host defense mechanisms for infection. A molecular understanding of E. ch. pathobiology will also facilitate development of novel therapeutic approaches for Ehrlichia spp. and intracellular pathogens that utilize SLiM mimicry or exploit conserved cellular pathways for infection and immune evasion.

摘要