The molecular response to environmental and physiological stress alerts cells to imminent danger and serves to protect the genetic and biosynthetic apparatus from sustaining potentially lethal proteotoxic damage. The heat shock response adjusts the levels of molecular chaperones to prevent the appearance and accumulation of aggregation-prone polypeptides during cell stress. At the center of this regulatory network, in larger eukaryotes, is a family of heat shock transcription factors (HSFs). Under conditions of normal cell growth, HSFs are repressed. In response to stress, HSFs are rapidly activated to induce the transcription of heat shock genes. The levels of chaperones are carefully balanced to reflect the levels of misfolded proteins and heat shock factor activity, such that the heat shock response is autoregulated and attenuates during recovery. This is a proposal for continued funding to: (1) Order the events associated with activation and attenuation of the heat shock response. The experiments would elucidate the process of intramolecular negative regulation of both the DNA binding and transactivation domains, the role of the molecular chaperone Hsp90 in maintenance of the inert monomer, the role of Hsp70/Hdj1 in transcriptional repression, the function of HSBP1 in the negative regulation of the heat shock response, and the characterization of other trans-regulators of HSF1. (2) Characterize the function of HSF1 stress granules in the cell biology of the heat shock response. Experiments are proposed to identify the targeting and retention signals involved in localization of HSF1 to stress granules, to identify the stress-regulated nuclear transport mechanism, to identify the chromosomal location of HSF1 granules, and to establish the role of HSF1 stress granules in the heat shock response. (3) Examine how different members of the family of heat shock factors coordinate their activities. Experiments are proposed to understand how the activities of HSF1 and HSF2 are coordinated under normal conditions of cell growth and stress and to establish the regulatory link between HSF2 lability and control by general protein degradation and the ubiquitin-dependent proteasome. (4) Characterize the C. elegans heat shock response to understand how stress responses are regulated in a multicellular differentiating organism. Dr. Morimoto will focus on tissue specific, developmental, and aging signals which modulate the heat shock response in C. elegans; the function of C. elegans HSF and trans-regulators, including heat shock proteins and HSB-1; and the relationship of the heat shock response to diseases of protein misfolding and protein aggregation, including Huntington's Disease and ALS. Proteins containing beta-hairpin stacked sheets will be expressed in C. elegans and human tissue culture cells (neuronal and non-neuronal), to understand the molecular basis of the """"""""stress signaling"""""""".

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37GM038109-17S2
Application #
6762258
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Anderson, James J
Project Start
1987-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
17
Fiscal Year
2003
Total Cost
$4,096
Indirect Cost
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Kirstein, Janine; Arnsburg, Kristin; Scior, Annika et al. (2017) In vivo properties of the disaggregase function of J-proteins and Hsc70 in Caenorhabditis elegans stress and aging. Aging Cell 16:1414-1424
Ciryam, Prajwal; Lambert-Smith, Isabella A; Bean, Daniel M et al. (2017) Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS. Proc Natl Acad Sci U S A 114:E3935-E3943
Labbadia, Johnathan; Morimoto, Richard I (2015) Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction. Mol Cell 59:639-50
Teixeira-Castro, Andreia; Jalles, Ana; Esteves, Sofia et al. (2015) Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Brain 138:3221-37
Labbadia, Johnathan; Morimoto, Richard I (2015) The biology of proteostasis in aging and disease. Annu Rev Biochem 84:435-64
Brandvold, Kristoffer R; Morimoto, Richard I (2015) The Chemical Biology of Molecular Chaperones--Implications for Modulation of Proteostasis. J Mol Biol 427:2931-47
van Oosten-Hawle, Patricija; Morimoto, Richard I (2014) Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling. Genes Dev 28:1533-43
Ryno, Lisa M; Genereux, Joseph C; Naito, Tadasuke et al. (2014) Characterizing the altered cellular proteome induced by the stress-independent activation of heat shock factor 1. ACS Chem Biol 9:1273-83
Roth, Daniela Martino; Hutt, Darren M; Tong, Jiansong et al. (2014) Modulation of the maladaptive stress response to manage diseases of protein folding. PLoS Biol 12:e1001998
Morimoto, Richard I; Cuervo, Ana Maria (2014) Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci 69 Suppl 1:S33-8

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