CHIP: A link between the chaperone and proteasome system

芯片：伴侣和蛋白酶体系统之间的联系

• 批准号: 8532680
• 负责人: Jonathan C. Schisler
• 金额: $ 29.69万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532680
• 关键词: Address; Attenuated; Biochemical; Biological; Biological Assay; Boxing; Cardiac; Cell model; Cell physiology; Cells; Cellular Stress; Cellular Stress Response; Complex; Cytoplasm; Data; Disease; Environment; Event; Family; Gap Junctions; Gene Expression Profile; Genes; Global Change; Goals; Grant; Health; Heat shock proteins; In Vitro; Knowledge; Link; Mediating; Metabolic; Modeling; Molecular; Molecular Biology Techniques; Molecular Chaperones; Molecular Conformation; Pathologic Processes; Pathway interactions; Performance; Physiological; Physiological Processes; Play; Positioning Attribute; Process; Proteins; Proteome; Quality Control; Reagent; Recovery; Recovery of Function; Regulation; Resistance; Role; Signal Transduction; Stress; Sum; System; Time; Ubiquitin; arm; biological adaptation to stress; cell growth regulation; design; in vivo; mRNA Expression; multicatalytic endopeptidase complex; novel; protein degradation; protein expression; protein folding; protein misfolding; prototype; public health relevance; response; stressor; therapeutic target; ubiquitin ligase

DESCRIPTION (provided by applicant): 70- and 90-kDa heat shock proteins (Hsps) are best known by their roles as molecular chaperones, participating in the folding, maturation, and proper subcellular targeting of nascent proteins or, conversely, the recovery of function of proteins that have been misfolded or otherwise damaged by cellular stressors. However, Hsps participate in a variety of processes- intracellular signaling events, proliferation, differentiation, and targeted degradation of proteins- that seem related to protein folding only indirectly, or not at all. At the same time, it is becoming increasingly apparent that molecular chaperones do not represent the sum total of the cell stress response, and that a range of events other than protein refolding are required to maintain viability and protect the intracellular environment in adverse circumstances. We identified CHIP (carboxyl-terminus of Hsc70-interacting protein) in a screen for stress-responsive genes in 1999. Since then, we have found that CHIP interacts with the chaperones Hsc70, Hsp70, and Hsp90 and has complex and coordinated effects on their functions. In addition, CHIP has ubiquitin ligase activity and plays a critical role in regulating protein quality control within the cytoplasm. Finally, we have found using both in vitro and in vivo approaches that CHIP is a central regulator of cellular and organismal stress responses. Surprisingly, at least some of these effects seem to be related to specific effects of CHIP on transcriptional, signaling, and metabolic responses. The aims of this grant are intended as a logical extension of our initial screen for proteins participating in molecular chaperone events. To accomplish our aims, we have formulated a novel and highly integrated approach using both in vitro and in vivo assays. The aims of this proposal are to: (1). Examine the consequences of CHIP on global changes in mRNA and protein expression in the context of cellular stress using a combined transcriptome/proteome analysis; (2) Characterize the role of CHIP on cell signaling and metabolic responses and (3) Evaluate the integrated effects of CHIP on pathophysiologic stress in vivo. The scope of this proposal is intended to address relevant biological and physiological questions using state of the art molecular biology techniques. Knowledge gained from this proposal should provide crucial information about how these various pathways regulate physiologic and pathologic processes that are under control of the ubiquitin/proteasome system and may provide potential therapeutic targets for treatment of diseases where this system is involved. PUBLIC HEALTH RELEVANCE: Proper protein folding is essential for optimum protein performance and normal cellular function. During synthesis of new proteins and refolding of denatured proteins, cooperation between the cell's molecular chaperones and its degradation machinery must occur because some proteins cannot attain their correct tertiary conformation spontaneously. The mutually exclusive pathways of folding and degradation constitute the cell's protein quality control system. The chaperone and ubiquitin-proteasome systems play critical roles in regulating stress-responsive signaling and cellular protective mechanisms in health and disease. Our overall goal is to determine how the molecular and physiologic functions of CHIP, a molecular chaperone, are coordinated to orchestrate its stress response capabilities. These studies will help us develop new models about the relationship between cytoplasmic quality control mechanisms and the cellular stress response.

描述（由申请人提供）：70-和 90-kDa 热休克蛋白 (Hsps) 最出名的是它们作为分子伴侣的作用，参与新生蛋白的折叠、成熟和适当的亚细胞靶向，或者相反，参与新生蛋白的恢复。被细胞应激源错误折叠或以其他方式损坏的蛋白质的功能。然而，热休克蛋白参与多种过程——细胞内信号传导事件、增殖、分化和蛋白质的靶向降解——这些过程似乎仅与蛋白质折叠间接相关，或者根本不相关。与此同时，越来越明显的是，分子伴侣并不代表细胞应激反应的总和，并且需要除蛋白质重折叠之外的一系列事件来维持活力并在不利环境下保护细胞内环境。我们于 1999 年在应激反应基因筛选中发现了 CHIP（Hsc70 相互作用蛋白的羧基末端）。此后，我们发现 CHIP 与伴侣 Hsc70、Hsp70 和 Hsp90 相互作用，并对它们的分子伴侣产生复杂且协调的影响。功能。此外，CHIP 具有泛素连接酶活性，在调节细胞质内的蛋白质质量控​​制中发挥着关键作用。最后，我们通过体外和体内方法发现 CHIP 是细胞和生物体应激反应的中心调节剂。令人惊讶的是，至少其中一些影响似乎与 CHIP 对转录、信号传导和代谢反应的特定影响有关。这笔资助的目的是作为我们对参与分子伴侣事件的蛋白质的初步筛选的逻辑延伸。为了实现我们的目标，我们利用体外和体内测定制定了一种新颖且高度集成的方法。本提案的目的是： (1).使用转录组/蛋白质组组合分析，检查 CHIP 对细胞应激背景下 mRNA 和蛋白质表达整体变化的影响； (2) 表征 CHIP 对细胞信号传导和代谢反应的作用；(3) 评估 CHIP 对体内病理生理应激的综合影响。该提案的范围旨在利用最先进的分子生物学技术解决相关的生物学和生理学问题。从该提案中获得的知识应提供有关这些不同途径如何调节泛素/蛋白酶体系统控制下的生理和病理过程的重要信息，并可能为涉及该系统的疾病的治疗提供潜在的治疗靶点。 公共健康相关性：正确的蛋白质折叠对于最佳蛋白质性能和正常细胞功能至关重要。在新蛋白质的合成和变性蛋白质的重折叠过程中，细胞的分子伴侣与其降解机制之间必须发生合作，因为某些蛋白质无法自发地获得其正确的三级构象。相互排斥的折叠和降解途径构成了细胞的蛋白质质量控​​制系统。伴侣和泛素蛋白酶体系统在调节健康和疾病中的应激反应信号传导和细胞保护机制中发挥着关键作用。我们的总体目标是确定 CHIP（分子伴侣）的分子和生理功能如何协调以协调其应激反应能力。这些研究将帮助我们开发关于细胞质质量控制机制与细胞应激反应之间关系的新模型。

项目成果

Overexpression of the cochaperone CHIP enhances Hsp70-dependent folding activity in mammalian cells.

辅助伴侣 CHIP 的过度表达增强了哺乳动物细胞中 Hsp70 依赖性折叠活性。

• 发表时间: 2003-07
• 影响因子: 5.3
• 作者: Kampinga, Harm H;Kanon, Bart;Salomons, Florian A;Kabakov, Alexander E;Patterson, Cam
• 通讯作者: Patterson, Cam

Structural basis of nucleotide exchange and client binding by the Hsp70 cochaperone Bag2.

Hsp70 辅助伴侣 Bag2 的核苷酸交换和客户结合的结构基础。

• 发表时间: 2008-12
• 影响因子: 16.8
• 作者: Xu, Zhen;Page, Richard C;Gomes, Michelle M;Kohli, Ekta;Nix, Jay C;Herr, Andrew B;Patterson, Cam;Misra, Saurav
• 通讯作者: Misra, Saurav

Hold me tight: Role of the heat shock protein family of chaperones in cardiac disease.

抱紧我：伴侣热休克蛋白家族在心脏病中的作用。

• 发表时间: 2010-10-26
• 影响因子: 37.8
• 作者: Willis, Monte S;Patterson, Cam
• 通讯作者: Patterson, Cam

NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo.

NF-κB 抑制可防止体内肿瘤引起的心肌萎缩。

• 发表时间: 2011-03
• 作者: Wysong, Ashley;Couch, Marion;Shadfar, Scott;Li, Luge;Li, Lugi;Rodriguez, Jessica E;Asher, Scott;Yin, Xiaoying;Gore, Mitchell;Baldwin, Al;Patterson, Cam;Willis, Monte S
• 通讯作者: Willis, Monte S

CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70.

通过底物和 Hsp70 的连续泛素化进行 CHIP 介导的应激恢复。

• 发表时间: 2006-03-23
• 影响因子: 64.8
• 作者: Qian, Shu;McDonough, Holly;Boellmann, Frank;Cyr, Douglas M;Patterson, Cam
• 通讯作者: Patterson, Cam