IKKa-Dependent Negative Feedback Control of Non-Canonical NF-kB Activation

非典型 NF-kB 激活的 IKKa 依赖性负反馈控制

• 批准号: 8039043
• 负责人: GENHONG CHENG
• 金额: $ 22.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039043
• 关键词: Autoimmune Diseases; Autoimmune Process; B-Cell Lymphomas; B-Lymphocytes; Biochemical; Cells; Complex; Data; Diffuse; Disease; Feedback; Fibroblasts; Future; Generations; Genes; Genetic Transcription; Goals; Grant; Hour; Hyperactive behavior; IKK alpha; Immune; Interphase Cell; Kinetics; Lead; Ligation; Lymphoid Tissue; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Molecular; Multiple Myeloma; NF-kappa B; Osteoclasts; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Process; Receptor Activation; Regulation; Reporting; Rest; Role; Signal Pathway; Signal Transduction; Stimulus; Systemic Lupus Erythematosus; TNFRSF5 gene; TRAF2 gene; Time; Work; base; cell type; dimer; inhibitor/antagonist; macrophage; member; novel; prevent; receptor; transcription factor

DESCRIPTION (provided by applicant): Dimeric NF-:B transcription factors play critical roles in a wide variety of immune processes. Cytosolically sequestered in resting cells, NF-:B dimers are released to initiate gene transcription through the action of two basic signaling pathways known as the canonical and non-canonical NF-:B signaling pathways. These two pathways lead to release of NF-:B dimers on vastly different time scales and are regulated distinctly. While canonical NF-:B signaling is activated within minutes by a large number of receptors on a wide variety of cell types, non-canonical NF-:B signaling is activated over hours by a select group of receptors such as BAFF, LT2R, CD40 and RANK on a limited number of cell types such as B-cells, fibroblasts, and macrophages. However, both of these pathways play critical, non-redundant roles in the generation and survival of B-cells, osteoclasts, and secondary lymphoid tissues. It is now appreciated that hyperactivity of both canonical and non-canonical NF-:B signaling can lead to a variety autoimmune and proliferative diseases including Systemic Lupus Erythematosus, Multiple Myeloma, and Diffuse B-cell Lymphoma. While multiple negative feedback mechanisms have been described in the case of canonical NF-:B signaling which serve to terminate signaling and prevent pathological hyperactivation, no negative feedback mechanisms have been described for the non- canonical NF-:B signaling pathway. Our preliminary studies have demonstrated that IKK1, activated by NIK, can induce not only p100 phosphorylation and processing but also phosphorylation and destabilization of NIK. We have further mapped the IKK1 phosphorylation sites in NIK and shown that disruption of IKK1-dependent NIK phosphorylation can significantly increase NIK levels after receptor activation. Based on these preliminary results, we hypothesize that while previously reported TRAF-cIAP complex is responsible for NIK degradation in unstimulated cells, this novel IKK1-dependent NIK phosphorylation and destabilization mechanism plays an important negative feedback role in regulating non-canonical NF-:B activity after receptor activation. The goal of this R21 grant is to unravel the molecular components and mechanisms by which this feedback occurs. We propose to first identify the additional molecular components functioning within NIK-IKK1 feedback complex, then determine how these components assemble within the stimulus-induced NIK degradative complex, and finally determine the role of this feedback mechanism in regulation of both canonical and non-canonical NF-:B signaling. Together, we believe these studies will significantly enhance our understanding of non-canonical NF- :B regulation. Given the pathological potential of this pathway's hyperactivity in causing autoimmune diseases and cancers, further understanding of the molecular factors, biochemical relationships, and functional roles of negative feedback within the pathway will assist in future attempts to pharmacologically intervene in the pathway's activity. PUBLIC HEALTH RELEVANCE: It is now appreciated that hyperactivity of the non-canonical NF-:B pathway can lead to a variety autoimmune diseases such as Systemic Lupus Erythematosus and cancers including Multiple Myeloma and Diffuse B-cell Lymphoma. The goal of this R21 grant is to unravel the molecular components and mechanisms responsible for a novel feedback control pathway within non-canonical NF-kB signaling which we have identified based on our recent exciting preliminary results. We believe further understanding of the molecular factors, biochemical relationships, and functional roles of negative feedback within the non-canonical NF- :B pathway will assist in future attempts to pharmacologically intervene in treating autoimmune diseases and cancers.

描述（由申请人提供）：二聚体 NF-:B 转录因子在多种免疫过程中发挥着关键作用。 NF-:B 二聚体被隔离在静息细胞的胞浆中，通过两种基本信号传导途径（称为经典和非经典 NF-:B 信号传导途径）的作用释放以启动基因转录。这两条途径导致 NF-:B 二聚体在截然不同的时间尺度上释放，并且受到明显的调控。典型的 NF-:B 信号传导在几分钟内被多种细胞类型上的大量受体激活，而非典型的 NF-:B 信号传导则被一组选定的受体（例如 BAFF、LT2R、CD40）在数小时内激活对有限数量的细胞类型（例如 B 细胞、成纤维细胞和巨噬细胞）进行 RANK 和 RANK。然而，这两条途径在 B 细胞、破骨细胞和次级淋巴组织的生成和存活中都发挥着关键的、非冗余的作用。现在人们认识到，经典和非经典 NF-:B 信号传导的过度活跃可导致多种自身免疫和增殖性疾病，包括系统性红斑狼疮、多发性骨髓瘤和弥漫性 B 细胞淋巴瘤。虽然在规范 NF-:B 信号传导的情况下已经描述了多种负反馈机制，其用于终止信号传导并防止病理性过度激活，但尚未描述非规范 NF-:B 信号传导途径的负反馈机制。我们的初步研究表明，NIK 激活的 IKK1 不仅可以诱导 p100 磷酸化和加工，还可以诱导 NIK 磷酸化和不稳定。我们进一步绘制了 NIK 中 IKK1 磷酸化位点的图谱，并表明破坏 IKK1 依赖性 NIK 磷酸化可以在受体激活后显着提高 NIK 水平。基于这些初步结果，我们假设虽然之前报道的 TRAF-cIAP 复合物负责未刺激细胞中的 NIK 降解，但这种新型 IKK1 依赖性 NIK 磷酸化和去稳定机制在调节非经典 NF-:B 中发挥着重要的负反馈作用受体激活后的活性。 R21 资助的目标是揭示这种反馈发生的分子成分和机制。我们建议首先确定 NIK-IKK1 反馈复合物中起作用的其他分子成分，然后确定这些成分如何在刺激诱导的 NIK 降解复合物中组装，最后确定这种反馈机制在规范和非规范调节中的作用NF-:B 信号传导。总之，我们相信这些研究将显着增强我们对非规范 NF-:B 调节的理解。鉴于该通路过度活跃导致自身免疫性疾病和癌症的病理潜力，进一步了解该通路内负反馈的分子因素、生化关系和功能作用将有助于未来尝试药理学干预该通路的活性。 公共健康相关性：现在人们认识到，非典型 NF-:B 通路的过度活跃可导致多种自身免疫性疾病，例如系统性红斑狼疮和癌症，包括多发性骨髓瘤和弥漫性 B 细胞淋巴瘤。这项 R21 资助的目标是揭示非规范 NF-kB 信号传导中负责新型反馈控制途径的分子成分和机制，我们根据最近令人兴奋的初步结果确定了该途径。我们相信，进一步了解非经典 NF-:B 通路中负反馈的分子因素、生化关系和功能作用将有助于未来尝试药物干预治疗自身免疫性疾病和癌症。