Regulation of TNFa signaling

描述(申请人提供)：我们研究的长期目标是调查细胞内信号电路是如何对特定的细胞外刺激做出反应的，从而确定预防和治疗人类疾病的潜在治疗靶点。在这项研究中，我们将研究锌指蛋白Miz1--JNK信号体中一种新的信号和通路特异性调节器(SMOR)--选择性调节TNFpha诱导的JNK激活的分子机制以及这一调控的病理生理学意义。利用多方面的方法，我们最近发现Miz1作为一种新的信号和途径特异性调节器(SMOR)对TNFpha诱导的JNK激活进行负性调节。Miz1抑制TRAF2的K63连接的泛素化，从而只抑制JNK的激活，而不抑制ERK、p38或ikk的激活，并且只抑制由TNFpha激活的JNK，而不抑制IL-1、UV、TPA或其他JNK激活剂。在TNFpha刺激下，Miz1经历泛素化和随后的蛋白酶体降解，从而解除其抑制。我们推测Miz1是肿瘤坏死因子-R1复合体1的一个新的成分，在调节肿瘤坏死因子α信号转导中起关键作用。这一建议是新颖的，因为它将研究Miz1作为肿瘤坏死因子-R1复合体1的一个新成分的功能，研究Miz1是否决定了TNFpha激活的JNK和IKK之间的动力学差异，并确定了Miz1介导的抑制体内TNFpha信号的病理生理功能。这项研究将提出一种新的研究范式，探讨调节肿瘤坏死因子-1复合体激活的分子机制，并更好地理解调节肿瘤坏死因子-α信号的分子基础，而肿瘤坏死因子-α信号在许多人类疾病的炎症中起重要作用。

DESCRIPTION (provided by applicant): The long-term goal of our research is to investigate how the intracellular signaling circuitry is wired in response to specific extracellular stimuli, thereby identifying potential therapeutic targets for prevention and treatment of human diseases. In this proposal, we will study the molecular mechanism by which the zinc finger protein Miz1, a novel signal- and pathway- specific modulators or regulators (SMOR) in the JNK signalsome, selectively regulates TNFalpha-induced JNK activation and the pathophysiological implications of this regulation. Using multifaceted approaches, we have recently discovered that Miz1 acts as a novel signal- and pathway-specific modulators or regulators (SMOR) to negatively regulate TNFalpha- induced JNK activation. Miz1 suppresses TNFalpha-induced K63-linked polyubiquitination of TRAF2, thereby only inhibiting activation of JNK but not ERK, p38 or IKK by TNFalpha, and only JNK activation by TNFalpha but not IL-1, UV, TPA, or other JNK activators. Upon TNFalpha stimulation, Miz1 undergoes ubiquitination and subsequent proteasomal degradation, thereby relieving its inhibition. We hypothesize that Miz1 is a novel component of TNF-R1 Complex 1 and plays a critical role in regulation of TNFalpha signaling. This proposal is novel, as it will study how Miz1 functions as a novel component of TNF-R1 Complex 1, to study whether Miz1 determines the kinetic difference between TNFalpha- activated JNK and IKK, and to determine the pathophysiological functions of Miz1-mediated inhibition on the TNFalpha signlaing in vivo. This study will put forward a novel paradigm regarding the molecular mechanism by which activation of TNF-R1 Complex is regulated and will provide a better understanding of the molecular basis underlying regulation of TNF-alpha signaling, which is important in inflammation in many human diseases.