The heat shock (HS) response is the primary cellular defense mechanism against adverse environmental conditions. The hallmark of the HS response is the rapid and robust induction of HS genes, many of which encoding molecular chaperones. Heat shock proteins (HSPs) have been also implicated in a variety of pathological situations including cancer, ischemia/reperfusion, inflammation, etc. In eukaryotes the HS gene regulation occurs mainly at the transcriptional level by a family of heat shock transcription factors (HSFs), among which HSF1 is the master regulator. HSF1 is constitutively expressed in vertebrates as inactive monomer under tight negative regulation. Rapid and robust post- translational activation of HSF1 occurs in response to HS conditions and other stressors. Activation of HSF1 involves trimerization and acquisition of the DNA-binding activity, changes in phosphorylation pattern and acquisition of transactivation competence. Despite extensive research, the mechanism of HSF1 activation, especially at the trimerization step, remained elusive. During our extensive preliminary work we have identified two cellular factors that are essential for HSF1 activation: translation elongation factor eEF1A and a novel large non-coding RNA termed HSR1. HSR1 is shown to serve as a cellular thermosensor, whereas eEF1A serves a general sensor of protein integrity. The long-term objective of the present proposal is to provide a comprehensive physiological and mechanistic description of HSF1 activation and its regulation by HSR1/eEF1A sensor machinery. Specifically we propose to perform extensive structure-function characterization of HSF1-eEF1A- HSR1 ternary complex and unravel the mechanism underlying HSF activation by HSR1/eEF1A in response to various types of physical and chemical stressors in mammalian and Drosophila cells.

Public Health Relevance

We have shown that bacterial NO synthase (bNOS) generates NO in response to antibiotic treatment or macrophage attack, which greatly enhances bacterial survival. The mechanism of NO-mediated protection is complex and requires further investigation. Elucidation of this mechanism will assist in a rational improvement of many existing antibiotics and identification of novel drug targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI090110-04
Application #
8468101
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Davidson, Wendy F
Project Start
2010-05-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$393,179
Indirect Cost
$160,529
Name
New York University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Serganov, Alexander; Nudler, Evgeny (2013) A decade of riboswitches. Cell 152:17-24
Shamovsky, Ilya; Nudler, Evgeny (2009) Isolation and characterization of the heat shock RNA 1. Methods Mol Biol 540:265-79