Role of TRAF1 in signaling by TNFR2 family members

描述（由申请人提供）：肿瘤坏死因子（TNF）及其同源物在一系列广泛的生物过程中发挥重要作用，包括急性期反应、细胞生长和凋亡、炎症和淋巴细胞激活。 TNF有两种受体：TNFR1和TNFR2。 TNFR2 代表具有细胞内区域的跨膜蛋白家族，其缺乏死亡结构域。每种TNFR2家族受体可与一个或多个TRAF信号转导分子结合。 TRAF2、TRAF3、TRAF5 和 TRAF6 被证明参与信号转导和 NF-kappaB 和 AP-1 转录因子的激活。人们对 TRAF1 的功能知之甚少，只是它主要在活化的淋巴细胞中表达，并且与 TNFR 家族的许多不同成员相关，包括 TNFR2、CD27、CD30、4-1BB、OX-40、HVEM、TRANCE-R、XEDAR、AITR 等。 TRAF1 还与 Epstein-Barr 病毒 (EBV) 的潜伏膜蛋白 1 (LMP1) 结合。为了阐明 TRAF 1 的功能，我们培育了 TRAF 1 缺陷小鼠。与野生型 T 细胞相比，TRAF1 缺陷型 T 细胞在抗 CD3 刺激下表现出显着增加的增殖。来自 TRAF1 缺陷小鼠（而非正常同窝小鼠）的激活 T 细胞通过增殖和激活 NF-κB 和 AP-1 对 TNF 作出反应。此外，TRAF1 缺陷小鼠的皮肤对 TNF 诱导的 T 细胞介导的坏死高度敏感。总而言之，这些发现表明 TRAF1 是 TNF 信号传导的负调节因子。我们建议应用最先进的知识和技术来进一步了解 T 和 B 淋巴细胞中的 TRAF1 功能。我们计划解决三个重要问题： 1. TRAF1负调控TNFR2信号传导的精确生化机制是什么？我们将研究TRAF1抑制TNFR2信号传导的分子机制。我们将确定TRAF1在没有TNFR1的情况下TNFR2的信号转导中的作用以及在没有TNFR2的情况下TNFR1的信号转导中的作用。为此，我们将 TRAF1 缺陷小鼠与 TNFR1 或 TNFR2.2 缺陷小鼠进行繁殖。 TRAF1 可能对 T 细胞上表达的 TNFR2 家族的其他成员（包括 OX40、4-1bb、CD30 和 CD27）具有类似的功能。然而，与 OX40-/- 小鼠相反，TRAF1-/- 小鼠在过敏性哮喘模型中表现出高反应性。我们建议在体外和体内确定TRAF1在OX40信号传导中的作用。3． TRAF1 在 EBV LMP1 信号传导中发挥什么作用？我们将分析 TRAF1 在 EBV LMP1 信号传导和 B 细胞中的作用。

DESCRIPTION (provided by applicant): Tumor Necrosis Factor (TNF) and it homologues play important roles in a wide array of biological processes including the acute phase response, cell growth and apoptosis, inflammation and lymphocyte activation. TNF has two receptors: TNFR1and TNFR2. TNFR2 represent a family of transmembrane proteins with intracellular region, which lack a death domain. Each of TNFR2 family receptors may associate with one or several TRAF signal transduction molecules. TRAF2, TRAF3, TRAF5, and TRAF6 were shown to participate in signal transduction and activation of NF-kappaB and AP-1 transcription factors. Little is known about TRAF1 function except it is predominantly expressed in activated lymphocytes and is associated with a number of distinct members of the TNFR family, including TNFR2, CD27, CD30, 4-1BB, OX-40, HVEM, TRANCE-R, XEDAR, AITR and others. TRAF1 also binds to latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). To elucidate the function of TRAF 1 we have generated TRAF 1-deficient mice. Compared to wild type T cells, TRAF1-deficient T cells exhibit markedly increased proliferation to anti-CD3 stimulation. Activated T cells from TRAF1-deficient mice, but not from their normal littermates, responded to TNF by proliferation and activation of NF-kappaB and AP-1. Furthermore, skin from TRAF1-deficient mice was hypersensitive to TNF-induced T-cell mediated necrosis. Taken together, these findings suggest that TRAF1 is a negative regulator of TNF signaling. We propose to apply state of the art knowledge and techniques to further understand TRAF1 function in T and B lymphocytes. We plan to address three important questions: 1. What is the precise biochemical mechanism of TRAF1 negative regulation of TNFR2 signaling? We will study the molecular mechanism of inhibition of TNFR2 signaling by TRAF1. We will determine the role of TRAF1 in signal transduction by TNFR2 in the absence of TNFR1 and signal transduction by TNFR1 in the absence of TNFR2. For this purpose we will breed TRAF1-deficient mice with mice deficient in TNFR1 or TNFR2.2. TRAF1 might have similar function for other members of TNFR2 family expressed on T cells, including OX40, 4- 1bb, CD30, and CD27. Then again, TRAF1-/- mice, in opposite to OX40-/- mice, were hyperresponsive in a model of allergic asthma. We propose to determine the role of TRAF1 in OX40 signaling in vitro and in vivo.3. What is the role of TRAF1 in signaling by EBV LMP1? We will analyze the role of TRAF1 in EBV LMP1 signaling and B cell.