The COP9 Signalosome in the Heart

描述(申请人提供)：泛素蛋白酶体系统(UPS)负责细胞中大多数蛋白质的降解。通过清除异常蛋白质和去除不再需要的正常蛋白质，UPS介导的蛋白分解在细胞质量控制和细胞内稳态调节方面发挥着极其重要的作用，从而几乎触及细胞的每一个角落。最近的研究表明，UPS在心脏中的蛋白分解功能会因心脏衰竭时经常观察到的异常蛋白质聚集而严重受损，这表明UPS功能障碍可能在充血性心力衰竭(CHF)的进展中发挥极其重要的作用，CHF是一种影响数百万美国人健康和生活的临床综合征。因此，一个潜在的新治疗策略是使充血性心力衰竭患者心脏的UPS功能正常化。要做到这一点，必须首先阐明UPS功能的调节机制。本研究的一个长期目标是阐明UPS调节哺乳动物心脏蛋白质周转的分子机制，为利用UPS的蛋白降解功能治疗CHF提供分子生物学基础。最近发现的一个蛋白质复合体，COP9信号体(CSN)，由8个独特的蛋白质亚基组成(CSN1约为CSN8)，在真核生物中是进化保守的。来自低等生物和培养的哺乳动物细胞的研究表明，CSN在许多基本的细胞过程中发挥着重要作用，包括调节UPS的活性。这项研究将验证一个中心假设，即CSN与基于cullin的泛素E3连接酶合作破坏调节蛋白，同时抑制蛋白酶体对异常蛋白的降解；因此，CSN是心肌细胞生存、出生后心脏发育和心脏功能所必需的。通过条件性基因打靶，已经产生了CSN亚型小鼠品系，并实现了新生阶段心肌细胞对CSN基因的限制性敲除。然后将确定CSN心脏功能丧失或功能降低对心脏结构和功能的影响及其对心脏UPS功能的调节。这将为了解CSN在心脏中的功能以及CSN对心脏中UPS功能的依赖调节提供重要的见解。最终，这将有助于寻找新的措施来预防和/或更有效地治疗人类心力衰竭。

DESCRIPTION (provided by applicant): The ubiquitin proteasome system (UPS) is responsible for the degradation of most proteins in the cell. By clearing abnormal proteins and removing normal proteins that are no longer needed, UPS-mediated proteolysis plays an extremely important role in both quality control of the cell and regulation of the intracellular homeostasis, thereby touching virtually every corner of the cell. Recent studies have revealed that UPS proteolytic function in the heart can be severely impaired by abnormal protein aggregation which is often observed in failing human hearts, suggesting that UPS dysfunction may play an extremely important role in the progression of congestive heart failure (CHF), a clinical syndrome that affects the health and life of millions of Americans. Therefore, a potential new therapeutic strategy is to normalize UPS function in the heart with CHF. In order to do so, the mechanisms that regulate UPS function must first be elucidated. A long term goal of this proposal is to delineate the molecular mechanisms that regulate protein turnover in mammalian hearts by the UPS and provide molecular biology basis for harnessing UPS proteolytic function to treat CHF. A recently discovered protein complex, the COP9 signalosome (CSN) consisting of 8 unique protein subunits (CSN1 approximately CSN8), is evolutionary conserved throughout the eukaryotes. Studies from lower organisms and cultured mammalian cells have shown that CSN plays important roles in many basic cellular processes including regulating the activity of the UPS. This study will test a central hypothesis that CSN cooperates with cullin-based ubiquitin E3 ligases in destruction of regulatory proteins while it suppresses the degradation of abnormal proteins by the proteasome; therefore, it is required for heart muscle cell survival, postnatal cardiac development, and cardiac function. Through conditional gene targeting, a CSN hypomorphic mouse strain has been generated and the heart muscle cells restricted knockout of a CSN gene at the neonatal stage has also been achieved. The impact of CSN loss-of-function or reduced function in the heart on cardiac structure and function and its modulation of the UPS function in the heart will then be defined. This will provide important insights into the function of CSN in the heart and CSN-dependent regulation of UPS functions in the heart. Ultimately, this will help search for new measures to prevent and/or more effectively treat human CHF.