Receptor Kinase-Mediated Signaling in the Innate Immune Response

先天免疫反应中受体激酶介导的信号传导

基本信息

批准号：
8040928
负责人：
PAMELA C RONALD
金额：
$ 30.26万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-01-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8040928
关键词：
Affect Affinity Aftercare Amino Acids Animal Experiments Animals Binding Sites Cell Nucleus Cell Surface Receptors Cell physiology Cleaved cell Complex Cytoplasmic Tail Development Disease Event Extracellular Domain Family Gene Targeting Genes Genetic Transcription Gram-Negative Bacteria Immune response Immunity Inorganic Sulfates Lead Leucine-Rich Repeat Ligands Mediating Modeling Molecular Natural Immunity Nuclear Nuclear Translocation Oryza Pathway interactions Pattern Peptides Perception Phosphorylation Phosphotransferases Plants Play Process Protein Kinase Protein phosphatase Proteins Public Health Regulation Resistance Rice Role Serine Signal Transduction Signaling Protein Specificity Testing Transcriptional Regulation Unspecified or Sulfate Ion Sulfates Xanthomonas base defense response extracellular interest pathogen protein phosphatase 2C public health relevance receptor

项目摘要

DESCRIPTION (provided by applicant): Perception of extracellular signals by cell surface receptors is of central importance to eukaryotic development and immunity. Many of these receptors possess intrinsic protein kinase activity in their cytoplasmic domains (RKs) and regulate transcription of target genes through phosphorylation events. Abnormal regulation can lead to a variety of diseases and it is therefore important to understand how RK specificity and function are controlled. The rice Xa21 RK is a key recognition and signaling determinant in the innate immune response, a pathogen defense pathway widely conserved between plants and animals. XA21 serves as a pathogen recognition receptor (PRR) with leucine rich repeats (LRRs) in the extracellular domain and a non-RD kinase domain. Xa21 activity is triggered upon recognition of the pathogen-associated molecular pattern (PAMP) AvrXa21, a sulfated peptide that is produced by the Gram-negative bacterium Xanthomonas oryzae pv. oryzae. We have shown the XA21 JM domain plays a key role in XA21 kinase-mediated signal transduction. In particular, the XA21 JM amino acid residue serine 697 is critical for both positive and negative regulatory functions. When S697 is dephosphorylated, XA21-mediated resistance is enhanced. Upon phosphorylation, S697 serves as a high affinity-binding site for the downstream negative regulators, XB10 and XB15. We and others have also shown that XA21 is cleaved at the JM domain after treatment with Xoo strains carrying AvrXa21. We hypothesize that, upon AvrXa21-triggered cleavage, the XA21 kinase domain is translocated to the nucleus where it affects downstream signaling through interaction with Xb10 and other proteins. To further test this hypothesis we propose to: 1. Explore AvrXa21-dependent translocation of the XA21 kinase domain to the nucleus. 2. Further characterize the role of XA21S697 JM residue in XA21-mediated resistance. 3. Identify nuclear complexes that form after AvrXa21 activation RKs are an important class of molecules that mediate fundamental processes in both plants and animals. Regulation of RK signaling through the JM domain is so far unique to only a few receptor families controlling important cellular processes and consequently there is great interest in exploring the molecular basis for this control. The proposed studies will enhance our understanding of the role of JM domain cleavage and nuclear translocation of the liberated cytoplasmic domain. Because the XA21 PRR is a model for non-RD mediated innate immunity and receptor-kinase mediated signaling in plants and animals, the experiments proposed here will be broadly applicable to public health. PUBLIC HEALTH RELEVANCE: Perception of extracellular signals by cell surface receptors is of central importance to eukaryotic development and immunity. Many of these receptors possess intrinsic protein kinase activity in their cytoplasmic domains (RKs) and regulate transcription of target genes through phosphorylation events. Abnormal regulation can lead to a variety of diseases and it is therefore important to understand how RK specificity and function are controlled.

描述（由申请人提供）：细胞表面受体对细胞外信号的感知对于真核发育和免疫至关重要。这些受体中的许多受体在其细胞质结构域（RKS）中具有内在的蛋白激酶活性，并通过磷酸化事件调节靶基因的转录。异常调节会导致各种疾病，因此了解如何控制RK的特异性和功能。米XA21 RK是先天免疫反应中的关键识别和信号传导决定因素，这是一种在植物和动物之间广泛保守的病原体防御途径。 XA21用作病原体识别受体（PRR），具有富含亮氨酸的重复序列（LRR），在细胞外结构域和非RD激酶结构域中。 XA21活性是在识别与病原体相关的分子模式（PAMP）AVRXA21后触发的，这是一种由革兰氏阴性细菌Xanthomonas oryzae PV产生的硫酸化肽。 oryzae。我们已经显示XA21 JM结构域在XA21激酶介导的信号转导中起关键作用。特别是，XA21 JM氨基酸残基丝氨酸697对于正调控功能至关重要。当S697被脱磷酸化时，XA21介导的电阻会增强。磷酸化后，S697是下游负调节剂XB10和XB15的高亲和力结合位点。我们和其他人还表明，用携带AVRXA21的XOO菌株处理后，XA21在JM结构域上切割。我们假设，在AVRXA21触发的裂解上，XA21激酶结构域被转移到核中，该核通过与XB10和其他蛋白质相互作用而影响下游信号传导。为了进一步检验这一假设，我们提出：1。探索XA21激酶结构域依赖AVRXA21依赖性的易位。 2。进一步表征XA21S697 JM残基在XA21介导的电阻中的作用。 3。识别AVRXA21激活RKS后形成的核复合物是介导植物和动物基本过程的重要分子类别。到目前为止，通过JM域的调节RK信号传导仅是控制重要细胞过程的少数受体家族，因此对探索该对照的分子基础有极大的兴趣。拟议的研究将增强我们对JM结构域裂解和核转运的作用的理解。由于XA21 PRR是动植物中非RD介导的先天免疫和受体激酶介导的信号传导的模型，因此此处提出的实验将广泛适用于公共卫生。公共卫生相关性：细胞表面受体对细胞外信号的看法对于真核发展和免疫力至关重要。这些受体中的许多受体在其细胞质结构域（RKS）中具有内在的蛋白激酶活性，并通过磷酸化事件调节靶基因的转录。异常调节会导致各种疾病，因此了解如何控制RK的特异性和功能。