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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Membrane Biology and Protein Processing (MBPP)
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Gerratana, Barbara
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University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
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Schisler, Jonathan C; Grevengoed, Trisha J; Pascual, Florencia et al. (2015) Cardiac energy dependence on glucose increases metabolites related to glutathione and activates metabolic genes controlled by mechanistic target of rapamycin. J Am Heart Assoc 4:
Shi, Chang-He; Schisler, Jonathan C; Rubel, Carrie E et al. (2014) Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. Hum Mol Genet 23:1013-24
Ronnebaum, Sarah M; Patterson, Cam; Schisler, Jonathan C (2014) Minireview: hey U(PS): metabolic and proteolytic homeostasis linked via AMPK and the ubiquitin proteasome system. Mol Endocrinol 28:1602-15
Willis, Monte S; Bevilacqua, Ariana; Pulinilkunnil, Thomas et al. (2014) The role of ubiquitin ligases in cardiac disease. J Mol Cell Cardiol 71:43-53
Ronnebaum, Sarah M; Wu, Yaxu; McDonough, Holly et al. (2013) The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical ubiquitination. Mol Cell Biol 33:4461-72
Willis, Monte S; Min, Jin-Na; Wang, Shaobin et al. (2013) Carboxyl terminus of Hsp70-interacting protein (CHIP) is required to modulate cardiac hypertrophy and attenuate autophagy during exercise. Cell Biochem Funct 31:724-35
Schisler, Jonathan C; Rubel, Carrie E; Zhang, Chunlian et al. (2013) CHIP protects against cardiac pressure overload through regulation of AMPK. J Clin Invest 123:3588-99
Willis, Monte S; Patterson, Cam (2013) Proteotoxicity and cardiac dysfunction. N Engl J Med 368:1755
Radovanac, Korana; Morgner, Jessica; Schulz, Jan-Niklas et al. (2013) Stabilization of integrin-linked kinase by the Hsp90-CHIP axis impacts cellular force generation, migration and the fibrotic response. EMBO J 32:1409-24
Willis, Monte S; Dyer, Laura A; Ren, Rongqin et al. (2013) BMPER regulates cardiomyocyte size and vessel density in vivo. Cardiovasc Pathol 22:228-40

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