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; 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转录因子在各种免疫过程中起关键作用。 Nf-：B二聚体在静息细胞中隔离的胞质固体释放以启动基因转录，这是两个基本信号通路的作用，称为规范和非典型的NF-：B信号传导途径。这两种途径导致NF-：B二聚体在巨大不同的时间尺度上的释放，并明显受到调节。虽然规范的NF-：B信号在几分钟内被多种细胞类型的大量受体激活，但非典型的NF-：B信号传导被选定的受体（例如BAFF，LT2R，CD40）等小时激活数小时，并在有限的细胞类型上等级，例如B-Cells，B-Cells，fibroblasts和fibroblasts和MoClophages和Mocarpops和MoClophages。但是，这两种途径在B细胞，破骨细胞和次级淋巴组织的产生和存活中扮演着关键的非冗余角色。现在，人们认为，规范和非典型的NF-：B信号的多动症都可以导致自身免疫性和增生性疾病，包括全身性红斑狼疮，多发性骨髓瘤和弥漫性B细胞淋巴瘤。尽管在规范的NF-：B信号传导的情况下已经描述了多种负面反馈机制，该机制用于终止信号并防止病理过度激活，但未针对非规范的NF-：B信号通路描述了负反馈机制。我们的初步研究表明，由NIK激活的IKK1不仅可以诱导P100磷酸化和加工，还可以诱导NIK的磷酸化和磷酸化和不稳定。我们进一步绘制了NIK中的IKK1磷酸化位点，并表明IKK1依赖性NIK磷酸化的破坏可以显着增加受体激活后NIK水平。基于这些初步结果，我们假设，尽管先前报道的TRAF-CIAP复合物是导致未刺激细胞中NIK降解的，但这种新型的IKK1依赖性NIK磷酸化和破坏稳定机制在调节非循环NF-的受体活性后起着重要的负反馈作用。该R21赠款的目的是揭示发生反馈的分子成分和机制。我们建议首先确定在NIK-IKK1反馈复合物中起作用的附加分子成分，然后确定这些组件如何在刺激引起的NIK降解络合物中组装，并最终确定此反馈机制在规范和非canonical nf-nf-：b-：b信号的调节中的作用。我们共同认为，这些研究将大大增强我们对非经典NF-的理解。鉴于该途径在引起自身免疫性疾病和癌症方面的过度活动性的病理潜力，进一步了解分子因素，生化关系以及负反馈在途径中的功能作用将有助于未来的药理介入途径的尝试。 公共卫生相关性：现在人们赞赏非典型的NF-：B途径的多动症会导致多种自身免疫性疾病，例如全身性红斑狼疮和癌症，包括多发性骨髓瘤和弥漫性B细胞淋巴瘤。该R21赠款的目的是揭示导致非经典NF-KB信号内新型反馈控制途径的分子成分和机制，我们根据我们最近的激动人心的初步结果确定了该途径。我们认为，对非典型的NF-：B途径中负反馈的分子因素，生化关系以及功能作用的进一步理解将有助于将来尝试在药理学上干预治疗自身免疫性疾病和癌症。