Regulation of Histone Acetyltransferase Stability In Sepsis

 描述(申请人提供)：CREB结合蛋白(CBP)是一种多功能的组蛋白乙酰转移酶(HAT)，在包括败血症和肺部疾病在内的炎症性疾病中，它在促炎细胞因子基因转录调节中发挥关键作用。因此，选择性地调节CBP的可用性可以潜在地抑制细胞因子风暴，减轻脓毒症的严重程度。泛素-蛋白酶体系统处理细胞内的绝大多数蛋白质，包括CBP。泛素化是一个可逆的反应。由一组去泛素化酶介导的去泛素化I，通过从目标蛋白质中去除“降解”信号来增强蛋白质的稳定性。然而，CBP的去泛素化以前还没有被研究过。我们的初步数据显示，泛素特异性多肽酶(USP)14使CBP去泛素化并增强其稳定性，而抑制USP14可减弱内毒素增加的CBP稳定性、组蛋白乙酰化和细胞因子释放，从而减轻全身和肺部炎症。这是第一次发现一种调节HAT稳定性和生物学效应的脱泛素酶。本研究提示，USP14的抑制剂IU1是一种抗炎小分子，有可能用于脓毒症的新药治疗。这些研究的实施将为严重感染期间先天免疫反应的分子调控机制的重大进展奠定基础。

 DESCRIPTION (provided by applicant): CREB-binding protein (CBP) is a versatile histone acetyltransferase (HAT), which plays a crucial role in the regulation of pro-inflammatory cytokine gene transcription in inflammatory diseases including sepsis and lung disorders. Therefore, selectively modulating the availability of CBP can potentially suppress cytokine storm and lessen the severity of sepsis. The ubiquitin-proteasome system disposes of the vast majority of intracellular proteins, including CBP. Ubiquitination is a reversible reaction. De-ubiquitination i mediated by a group of de- ubiquitinating enzymes, which enhances protein stability by removing the "degradation" signal from the target proteins. However, the de-ubiquitination of CBP has not been previously investigated. Our preliminary data show that ubiquitin specific peptidase (USP)14 de-ubiquitinates CBP and enhances its stability, and that inhibition of USP14 attenuates LPS-increased CBP stability, histone acetylation, and cytokine release, thereby lessening both systemic and pulmonary inflammation. This is the first study to identify a de-ubiquitinating enzyme regulating stability and biological effects of a HAT. This study suggests that IU1, an inhibitor of USP14, is an anti-inflammatory small molecule potentially applicable in new medication for sepsis. Execution of these studies will lay the groundwork for a significant mechanistic advance for the molecular regulation of the innate immune response during severe infection.