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。在这个提议中，我们将研究锌指蛋白Miz 1，一种新的信号和途径特异性调节剂或调节剂（SMOR）在JNK信号体，选择性地调节TNFa诱导的JNK激活的分子机制和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Miz 1作为一种新的信号和途径特异性调节剂或调节剂（SMOR）负调节TNF α诱导的JNK激活。Miz 1抑制TNF α诱导的TRAF 2的K63连接的多聚泛素化，从而仅抑制TNF α对JNK的激活，但不抑制ERK、p38或IKK，并且仅抑制TNF α对JNK的激活，但不抑制IL-1、UV、TPA或其他JNK激活剂。在TNF α刺激后，Miz 1经历泛素化和随后的蛋白酶体降解，从而缓解其抑制。我们假设Miz 1是TNF-R1复合物1的一种新组分，在调节TNF α信号传导中起着关键作用。该提议是新颖的，因为它将研究Miz 1如何作为TNF-R1复合物1的新组分起作用，以研究Miz 1是否决定TNF α激活的JNK和IKK之间的动力学差异，并确定Miz 1介导的抑制体内TNF α信号传导的病理生理功能。这项研究将提出一个新的范式，关于TNF-R1复合物激活的分子机制进行调节，并将提供更好地了解TNF-α信号转导调节的分子基础，这在炎症中很重要 在许多人类疾病中。

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.