Receptor Kinase-Mediated Signaling in the Innate Immune Response

描述(申请人提供)：细胞表面受体对细胞外信号的感知对真核发育和免疫至关重要。这些受体中的许多在其细胞质结构域(RKS)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。调节异常可导致多种疾病，因此了解RK的特异性和功能是如何控制的是重要的。水稻Xa21 RK是天然免疫应答中的关键识别和信号决定子，天然免疫应答是植物和动物之间广泛保守的病原体防御途径。Xa21是一种病原体识别受体(PRR)，在胞外区和非RD激酶区含有富含亮氨酸的重复序列(LRR)。Xa21活性是在识别病原体相关分子模式(PAMP)AvrXa21后触发的，AvrXa21是一种由革兰氏阴性细菌Xanthomonas oryzae PV产生的硫酸化多肽。米饭。我们已经证明了XA21 JM结构域在XA21激酶介导的信号转导中起着关键作用。特别是，XA21 JM氨基酸残基丝氨酸697对于正负调节功能都是至关重要的。当S697去磷酸化时，Xa21介导的抗性增强。在磷酸化后，S697作为下游负调控子XB10和XB15的高亲和力结合位点。我们和其他人也表明，用携带AvrXa21的Xoo菌株处理后，Xa21在JM结构域被切割。我们假设，在AvrXa21触发的切割过程中，Xa21激动域被移位到细胞核，在那里它通过与Xb10和其他蛋白质的相互作用影响下游信号转导。为了进一步验证这一假说，我们建议：1.探索依赖AvrXa21的XA21激酶域到细胞核的易位。2.进一步研究XA21S697 JM残基在XA21介导的抗性中的作用。3.鉴定AvrXa21激活后形成的核复合体RKS是一类重要的分子，在植物和动物中都参与了基本的过程。到目前为止，通过JM结构域调节RK信号是只有少数控制重要细胞过程的受体家族所特有的，因此人们对探索这种控制的分子基础非常感兴趣。建议的研究将加强我们对JM结构域的作用的理解，以及释放的细胞质结构域的核转位。由于XA21PRR是动植物中非RD介导的先天免疫和受体激酶介导的信号转导的模型，因此本文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感知对真核细胞的发育和免疫至关重要。这些受体中的许多在其细胞质结构域(RKS)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。调节异常可导致多种疾病，因此了解RK的特异性和功能是如何控制的是重要的。

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.