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A Non-Canonical IRAK1 Signaling Pathway Triggered by Ionizing Radiation

电离辐射触发的非典型 IRAK1 信号通路

基本信息

批准号：
10197966
负责人：
Samuel Sidi
金额：
$ 34.75万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197966
关键词：
Acute Adaptor Signaling Protein Animals Apoptosis Binding Proteins Biological CASP2 gene Cancer Patient Cell Nucleus Cell Survival Cell division Cell surface Cells Cessation of life Clinical Collaborations Complex Cytoplasm DNA DNA Damage DNA Double Strand Break Data Death Domain Dose Drosophila genus Environment Genetic Screening Genotoxic Stress Human IRAK1 gene IRAK2 gene IRAK4 gene Immune signaling Immunity In Vitro Infection Inflammation Inflammatory Response Interleukin-1 Receptors Intrinsic drive Ionizing radiation Kinetics Location MAP Kinase Gene MAPK8 gene Malignant Neoplasms Mammals Mediating Modeling Molecular Monitor NF-kappa B Natural Immunity Nuclear Pathway interactions Pattern Phosphotransferases Preparation Process Proteins Proteomics Radiation Radiation therapy Receptor Signaling Reporting Resistance Role Scaffolding Protein Signal Pathway Signal Transduction Stimulator of Interferon Genes Stimulus Structure System TLR1 gene Tertiary Protein Structure Time Tin Toll-like receptors Transducers Ultraviolet Rays Vertebrates Work XRCC5 gene Zebrafish autocrine base biological adaptation to stress combat cytokine dimer environmental stressor fly improved outcome interleukin-1 receptor-associated kinase microbial new therapeutic target novel p38 Mitogen Activated Protein Kinase paracrine pathogen pressure receptor recruit response scaffold sensor spatiotemporal tumor ultraviolet irradiation

项目摘要

Project Summary Interleukin-1 Receptor (IL-1R)-Associated Kinase 1, IRAK1, is a core transducer of Toll-like receptor (TLR) and IL-1R-mediated innate immune signaling from flies to humans. In response to pathogen infection, ligated TLR/IL-R receptors almost instantaneously activate IRAK1 via formation of the MyDDosome complex (IL-1R/TLR—MyD88-IRAK4-IRAK1) at the cell surface. Once phosphorylated by IRAK4 and itself, fully activated IRAK1 dissociates from the platform and engages NF-kB and other signaling cascades, culminating in the acute inflammatory response. Until recently, vertebrate IRAK1 had not been implicated in processes other than the microbial response. In an unbiased zebrafish screen, we recently identified IRAK1 as essential for cell survival in response to ionizing radiation (gIR) (Liu et al., Nat Cell Biol 2019; ref. 1). This function is conserved in human cells and drives cellular resistance to radiotherapy (R-RT) in tumor models. Rather than acting to stimulate NF-kB, IRAK1 drives cell survival by countering apoptosis mediated by the PIDDosome complex (PIDD-RAIDD- caspase-2). In further contrast with canonical IRAK1/4 immune signaling, our preliminary data indicate that the IRAK1 response to gIR: (i) fully requires its kinase activity; (ii) does not require the IL-1R/TLR—IRAK1/4 adaptor MyD88; and most strikingly, (iii) initiates in the nucleus of irradiated cells and not at the cell surface. gIR-induced IRAK1 activation does however occur within minutes of stimulus and absolutely requires IRAK4, suggesting the existence of a novel oligomeric platform responsible for orchestrating gIR-induced IRAK1 activation in place of the MyDDosome. While the evidence convincingly points to a novel IRAK1 stress response pathway in vertebrates, the cellular and molecular bases of gIR-induced IRAK1 activation remain to be defined. In Aim 1, we will monitor the localization of both active and native IRAK1 as a function of time after gIR; identify the cellular signal(s) that effectively trigger IRAK1 activation in irradiated cells, with DNA breaks, micronucleation, cytokines and danger- associated molecular patterns (DAMPs) as primary candidates; and explore whether environmental stresses (e.g., UV irradiation) can trigger the pathway. In Aim 2, we will dissect the molecular mechanism of IRAK1 activation in response to gIR, first by focusing on the roles of IRAK4 and IRAK1 itself; second by identifying the DD protein substituting for MyD88 as scaffold for the gIR-induced IRAK4/IRAK1 activation platform; and finally taking unbiased, larger scale proteomic approaches toward the unbiased identification of the upstream sensors, transducers and regulators that orchestrate IRAK1 activation in irradiated nuclei. Beyond illuminating a novel stress response pathway in vertebrates, our proposal explores a pathway implicated in tumor R-RT. Thus, an additional immediate impact of our work might be the discovery of novel drug targets for overcoming R-RT in the majority of cancer patients that receive RT as part of their treatment.

项目摘要白细胞介素1受体相关激酶1（IL-1 R-Associated Kinase 1，IRAK 1）是Toll样受体的核心转导子 (TLR)以及从苍蝇到人类的IL-1 R介导的先天免疫信号。为了应对病原体感染，连接的TLR/IL-R受体通过形成MyDDosome复合物几乎立即激活IRAK 1 在细胞表面的IL-1 R/TLR-MyD 88-IRAK 4-IRAK 1。一旦被IRAK 4及其自身磷酸化，激活的IRAK 1从平台上解离并参与NF-κ B和其他信号级联，在急性炎症反应中。直到最近，脊椎动物IRAK 1还没有被牵连到过程中，除了微生物的反应。在一项无偏见的斑马鱼筛选中，我们最近发现IRAK 1对细胞存活至关重要，电离辐射（gIR）（Liu等人，Nat Cell Biol 2019;参考文献1）。这种功能在人类细胞中是保守的，在肿瘤模型中驱动细胞对放射疗法（R-RT）的抗性。而不是采取行动，以刺激NF-κ B， IRAK 1通过对抗由PIDDosome复合物（PIDD-RAIDD-1）介导的细胞凋亡来驱动细胞存活。半胱天冬酶-2）。与经典的IRAK 1/4免疫信号传导形成进一步对比，我们的初步数据表明， IRAK 1对gIR的反应：（i）完全需要其激酶活性;（ii）不需要IL-1 R/TLR-IRAK 1/4 衔接子MyD 88;最引人注目的是，（iii）在辐射细胞的细胞核中启动，而不是在细胞表面。然而，gIR诱导的IRAK 1活化在刺激的几分钟内发生并且绝对需要IRAK 4，提示存在一种新的寡聚体平台，负责协调gIR诱导的IRAK 1 激活MyDDosome。虽然有证据令人信服地指出脊椎动物中存在一种新的IRAK 1应激反应途径，但 gIR诱导的IRAK 1活化的细胞和分子基础仍有待确定。在目标1中，我们将监测活性和天然IRAK 1的定位作为gIR后时间的函数;鉴定有效地触发辐射细胞中的IRAK 1激活，DNA断裂，微核，细胞因子和危险- 相关的分子模式（DAMP）作为主要候选人;并探讨环境压力是否 (e.g.,紫外线照射）可以触发该途径。在目标2中，我们将剖析IRAK 1的分子机制。激活响应gIR，首先通过关注IRAK 4和IRAK 1本身的作用;其次通过识别 DD蛋白替代MyD 88作为gIR诱导的IRAK 4/IRAK 1活化平台的支架;以及最后采用无偏的、更大规模的蛋白质组学方法，传感器、转换器和调节器，协调辐照核中的IRAK 1激活。超越启发一种新的应激反应途径在脊椎动物中，我们的建议探讨了一个途径牵连在肿瘤R-RT。因此，我们工作的另一个直接影响可能是发现新的药物靶点，在接受RT作为其治疗的一部分的大多数癌症患者中，R-RT。