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: 8208992
• 负责人: GENHONG CHENG
• 金额: $ 18.69万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208992
• 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; public health relevance; 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（由申请方提供）：二聚NF-：B转录因子在多种免疫过程中发挥关键作用。NF-：B二聚体在静息细胞中被胞质隔离，通过称为经典和非经典NF-：B信号传导途径的两种基本信号传导途径的作用释放以启动基因转录。这两种途径导致NF-：B二聚体在非常不同的时间尺度上释放，并且受到明显的调节。虽然经典NF-：B信号传导在数分钟内被多种细胞类型上的大量受体激活，但非经典NF-：B信号传导在数小时内被有限数量的细胞类型（如B细胞、成纤维细胞和巨噬细胞）上的一组选定受体（如BAFF、LT 2 R、CD 40和RANK）激活。然而，这两种途径在B细胞、破骨细胞和次级淋巴组织的生成和存活中起着关键的、非冗余的作用。现在认识到，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性和增殖性疾病，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。虽然在典型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超活化，但是对于非典型NF-：B信号传导途径没有描述负反馈机制。我们的初步研究表明，IKK 1被NIK激活后，不仅可以诱导p100的磷酸化和加工，还可以诱导NIK的磷酸化和去稳定化。我们进一步绘制了NIK中IKK 1的磷酸化位点，并表明IKK 1依赖的NIK磷酸化的破坏可以显着增加受体激活后的NIK水平。基于这些初步结果，我们假设，虽然以前报道的TRAF-cIAP复合物是负责NIK降解在未刺激的细胞，这种新的IKK 1依赖性NIK磷酸化和不稳定的机制发挥了重要的负反馈作用，在调节非典型的NF-：B活性受体激活后。这项R21资助的目标是解开这种反馈发生的分子组成和机制。我们建议首先确定NIK-IKK 1反馈复合物中的其他分子组分，然后确定这些组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经典和非经典NF-：B信号传导调控中的作用。总之，我们相信这些研究将显著增强我们对非经典NF-：B调控的理解。鉴于该途径的过度活跃在导致自身免疫性疾病和癌症方面的病理学潜力，进一步了解该途径内负反馈的分子因素、生物化学关系和功能作用将有助于未来尝试对该途径的活性进行非干预性干预。 公共卫生关系：现在认识到，非经典NF-：B途径的过度活性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资助的目标是解开负责非经典NF-κ B信号传导中一种新的反馈控制途径的分子组分和机制，我们已经根据我们最近令人兴奋的初步结果确定了这些分子组分和机制。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、生物化学关系和功能作用将有助于将来尝试非特异性干预治疗自身免疫性疾病和癌症。