Sandy Westerheide
Sandy Westerheide
Assistant Professor
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Education
Ph.D., Emory University, Atlanta, GA, 1998
Postdoctoral Fellow, University of North Carolina, Chapel Hill, NC, 1998-2002
Postdoctoral Fellow, Northwestern University, Evanston, IL, 2002-2009
Research
Research in my laboratory is directed at understanding the molecular importance of the heat shock response (HSR) on cellular metabolism, aging and disease. The HSR is a universally conserved pathway that allows cells to recover from protein damage induced by heat stress, heavy metals, normal development, and disease states such as neurodegenerative disease and cancer. The heat shock transcription factor HSF1, the master regulator of the HSR, transcriptionally activates molecular chaperones and other genes that are essential for cell survival. We have found that HSF1 is positively regulated by the longevity factor SIRT1. SIRT1 is a metabolically regulated deacetylase that is required for full HSF1 transcription. In collaboration with Stan Stevens in the department, our work was the first to show that HSF1 is acetylated within its DNA binding domain at lysine 80, and that acetylation at this site disrupts DNA binding. Deacetylation of this residue by SIRT1 maintains HSF1 in a DNA-binding competent state, activating HSF1-dependent transcription and the HSR. Our work suggests that HSF1 and SIRT1 together compose a molecular network that connects cell metabolism, stress and lifespan.
Research Projects
1) Examine the effect of cellular metabolism and aging on the HSR
The identification of SIRT1 as a positive regulator of HSF1 transcription suggests that the HSR is likely controlled by metabolism during the aging process. To investigate the effects of aging and metabolism on the HSR, experiments are underway using low and high passage human fibroblasts to determine whether replicative lifespan alters the HSR-responsiveness in a SIRT1-dependent manner. Distinct metabolic pathways regulated by HSF1 and SIRT1 will be evaluated to determine how these two important proteins modulate cell fate networks in response to the HSR and aging.
2) Further define the mechanism of SIRT1 regulation of the HSR
Although we know that SIRT1 activity is required to regulate HSF1 transcription, the molecular mechanisms by which SIRT1 regulates HSF1 during HSR are not fully understood. As SIRT1 mRNA and protein levels do not change during the HSR, my laboratory is examining whether SIRT1 activity is post-translationally regulated by stress. We are testing whether HSR-inducing stressors alter SIRT1 cellular localization, activity and/or interaction with HSF1 during heat shock and metabolic stress. The goal of this project is to identify novel mechanisms by which SIRT1 activity is modulated by heat shock and other stressors.
3) Analyze the interplay of post-translational modifications on HSF1 function
HSF1 is a highly post-translationally modified protein that is hyperphosphorylated and SUMOylated. Working together with Stan Stevens, we have found that HSF1 is also hyperacetylated on 9 lysine resides following heat shock. Given that HSF1 is an essential transcription factor in controlling cell fate in response to multiple stress responses, it is likely that the various post-translational modifications of HSF1 generate a “code” that fine-tunes the HSR. We are unraveling the post-translational code of HSF1 using mass spectrometry and site-directed mutagenesis to determine the importance of these modifications. These studies will provide insight into how HSF1 activation is differentially regulated according to the stress signals, and will potentially allow determination of how HSF1 controls stress-specific gene expression in a cell-type specific manner.
Recent Publications
Sandy D. Westerheide*, Julius Anckar*, Stanley Stevens, Lea Sistonen and Richard I. Morimoto. Stress-Inducible Regulation of Heat Shock Factor 1 by the Deacetylase SIRT1. Science, 2009. 323(5917):1063 *co-first authors
Richard I. Morimoto and Sandy D. Westerheide. The heat shock response and the stress of misfolded proteins in the Handbook of Cell Signaling. Ralph Bradshaw and Edward Dennis, editors. (Elsevier, Inc., San Diego, California). 2009.
Amy Trott, James D. West, Lada Klaic, Sandy D. Westerheide, Richard B. Silverman, Richard I. Morimoto and Kevin A. Morano. Simultaneous activation of heat shock and oxidative stress pathways by celastrol. Mol Biol Cell, 2008. 19(3):1104
Sandy D. Westerheide*, Tiara L. Kawahara*, Kai Orton and Richard I. Morimoto. Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death. J Biol Chem, 2006. 281(30):21575 *co-first authors
Sandy D. Westerheide and Richard I. Morimoto. Heat shock modulators as therapeutic tools for diseases of protein conformation. J Biol Chem, 2005. 280(39):33097
Sandy D. Westerheide, Joshua D. Bosman, Bessie N. A. Mbadugha, Tiara L. A. Kawahara, Gen Matsumoto, Soojin Kim, Wenxin Gu, John P. Devlin, Richard B. Silverman, and Richard I. Morimoto. Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem, 2004. 279(53):56053