Regulation of TNFa signaling

描述（由申请人提供）：我们研究的长期目标是研究细胞内信号通路如何响应特定的细胞外刺激，从而确定预防和治疗人类疾病的潜在治疗靶点。在本研究中，我们将研究锌指蛋白Miz1的分子机制，锌指蛋白Miz1是JNK信号体中一种新的信号和通路特异性调节剂或调节剂（SMOR），它可以选择性地调节tnfalpha诱导的JNK激活以及这种调节的病理生理意义。使用多方面的方法，我们最近发现Miz1作为一种新的信号和通路特异性调节剂或调节剂（SMOR）负调控TNFalpha诱导的JNK激活。Miz1抑制TNFalpha诱导的K63-linked TRAF2的多泛素化，因此仅抑制JNK而不抑制TNFalpha对ERK、p38或IKK的激活，并且仅抑制TNFalpha对JNK的激活，而不抑制IL-1、UV、TPA或其他JNK激活剂。在TNFalpha刺激下，Miz1经历泛素化和随后的蛋白酶体降解，从而减轻其抑制作用。我们假设Miz1是TNF-R1复合物1的新成分，在调节TNFalpha信号传导中起关键作用。该方案新颖，将研究Miz1作为TNF-R1复合物1的新组分如何发挥作用，研究Miz1是否决定TNFalpha激活的JNK和IKK之间的动力学差异，以及确定Miz1介导的抑制TNFalpha信号在体内的病理生理功能。本研究将为调节TNF-R1复合物激活的分子机制提供一个新的范式，并将更好地理解tnf - α信号调控的分子基础，这在许多人类疾病的炎症中是重要的。

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.