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Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1
journal contribution
posted on 2016-01-15, 00:00 authored by Christopher
L. Moore, Mahender B. Dewal, Emmanuel E. Nekongo, Sebasthian Santiago, Nancy
B. Lu, Stuart S. Levine, Matthew D. ShouldersProteostasis in the cytosol is governed
by the heat shock response.
The master regulator of the heat shock response, heat shock factor
1 (HSF1), and key chaperones whose levels are HSF1-regulated have
emerged as high-profile targets for therapeutic applications ranging
from protein misfolding-related disorders to cancer. Nonetheless,
a generally applicable methodology to selectively and potently inhibit
endogenous HSF1 in a small molecule-dependent manner in disease model
systems remains elusive. Also problematic, the administration of even
highly selective chaperone inhibitors often has the side effect of
activating HSF1 and thereby inducing a compensatory heat shock response.
Herein, we report a ligand-regulatable, dominant negative version
of HSF1 that addresses these issues. Our approach, which required
engineering a new dominant negative HSF1 variant, permits dosable
inhibition of endogenous HSF1 with a selective small molecule in cell-based
model systems of interest. The methodology allows us to uncouple the
pleiotropic effects of chaperone inhibitors and environmental toxins
from the concomitantly induced compensatory heat shock response. Integration
of our method with techniques to activate HSF1 enables the creation
of cell lines in which the cytosolic proteostasis network can be up-
or down-regulated by orthogonal small molecules. Selective, small
molecule-mediated inhibition of HSF1 has distinctive implications
for the proteostasis of both chaperone-dependent globular proteins
and aggregation-prone intrinsically disordered proteins. Altogether,
this work provides critical methods for continued exploration of the
biological roles of HSF1 and the therapeutic potential of heat shock
response modulation.