Molecular Mechanisms Regulating Noncanonical NF-kB Signaling

描述（由申请人提供）：非规范NF-？B信号通路介导特异性NF-？B成员，p52和RelB，它们调节重要的生物学功能，如破骨细胞发生、淋巴样器官发生、淋巴细胞发育和活化以及免疫耐受的产生。这种新颖的NF-？B途径依赖于p52前体蛋白p100的加工。由于p100作为RelB的胞质抑制剂，p100加工过程不仅产生p52，而且还导致活性p52/RelB NF-？B复杂。在过去的几年里，我们已经取得了开创性的发现，证明p100的加工是通过由NIK和IKK1组成的新型激酶复合物的位点特异性磷酸化而受到严格调节的。我们的工作还揭示了由人类T细胞白血病病毒（HTLV）转化的白血病T细胞中异常的p100加工。本研究的总体目标是阐明调节正常和非规范NF-？B信号。拟议的项目是基于强有力的初步数据和发表的工作从我们的实验室。特别是，我们最近的工作提出了一种新的NIK调节机制，似乎涉及其与负调节因子TRAF3的动态相互作用及其表达水平的调节。有趣的是，诱导非典型NF-？B信号传导与TRAF3降解有关，尽管这一中间信号传导步骤是如何调控的尚不清楚。我们的初步研究还揭示了非典型NF-？B信号。此外，我们在了解非典型NF-?的病理激活方面取得了重大进展。被白血病病毒HTLV感染基于这些发现，我们假设非规范NF-？B信号传导受到负性和正性调节因子的严格控制，其失调可能导致免疫紊乱和htlv诱导的t细胞恶性肿瘤。我们将执行三个具体目标来检验我们的假设。(1)阐明调控NIK信号功能的生化机制。(2)表征非典型NF-的中间信号步骤和分子成分？B通路。(3)探讨非规范NF-？B途径在正常和病理t细胞活化中的作用。公共卫生相关性：NF-？B家族转录因子调节多种生物过程，最显著的是免疫和炎症反应。本研究项目的重点是了解NF-?的非典型（或非典型）信号通路。B激活。这一途径导致NF-？B是特异性适应性免疫功能所必需的，包括淋巴器官的形成、淋巴细胞的发育和激活。不受控非正则NF-？B信号传导与慢性炎症和自身免疫有关，而这一途径的缺陷会导致免疫缺陷。本申请中提出的研究涉及非典型NF-？B信号和将是重要的新的和有效的免疫疗法的发展。

DESCRIPTION (provided by applicant): The noncanonical NF-?B signaling pathway mediates activation of specific NF-?B members, p52 and RelB, which regulate important biological functions such as osteoclastogenesis, lymphoid organogenesis, lymphocyte development and activation, and generation of immunological tolerance. This novel NF-?B pathway relies on processing of the p52 precursor protein, p100. Since p100 functions as a cytoplasmic inhibitor of RelB, the p100 processing not only generates p52 but also causes nuclear translocation of active p52/RelB NF-?B complex. Over the past few years, we have made seminal pioneer findings demonstrating that the processing of p100 is tightly regulated through its site-specific phosphorylation by a novel kinase complex composed of NIK and IKK1. Our work also reveals the aberrant p100 processing in leukemia T cells transformed by the human T-cell leukemia virus (HTLV). The overall objective of this continuation application is to elucidate the molecular mechanisms mediating normal and deregulated noncanonical NF-?B signaling. The proposed project is based on strong preliminary data and published work from our laboratory. In particular, our recent work suggests a novel mechanism of NIK regulation, which appears to involve its dynamic interaction with a negative regulator, TRAF3, and modulation of its expression level. Intriguingly, induction of noncanonical NF-?B signaling is associated with TRAF3 degradation, although how this intermediate signaling step is regulated remains unclear. Our preliminary studies also reveal the involvement of novel regulators of noncanonical NF-?B signaling. Moreover, we have made significant progress towards understanding the pathological activation of noncanonical NF-?Bs by the leukemia virus HTLV. Based on these findings, we hypothesize that noncanonical NF-?B signaling is tightly controlled by negative and positive regulators, the deregulation of which may contribute to both immunological disorders and HTLV-induced T-cell malignancies. We will perform three specific aims to examine our hypotheses. (1) Elucidate the biochemical mechanisms that regulate the signaling function of NIK. (2) Characterize the intermediate signaling steps and molecular components of the noncanonical NF-?B pathway. (3) Investigate the role of noncanonical NF-?B pathway in normal and pathological T-cell activation. PUBLIC HEALTH RELEVANCE: The NF-?B family of transcription factors regulates diverse biological processes, most notably immune and inflammatory responses. The focus of this research project is to understand a noncanonical (or atypical) signaling pathway of NF-?B activation. This pathway leads to activation of a sub-group of NF-?B members and is required for specific adaptive immune functions, including lymphoid organ formation, lymphocyte development and activation. Uncontrolled noncanonical NF-?B signaling is linked to chronic inflammation and autoimmunity, whereas defect in this pathway causes immune deficiencies. The studies proposed in this application address the molecular mechanisms of noncanonical NF-?B signaling and will be important for the development of new and effective immune therapies.