TY - JOUR
T1 - Small-molecule proteostasis regulators for protein conformational diseases
AU - Calamini, Barbara
AU - Silva, Maria Catarina
AU - Madoux, Franck
AU - Hutt, Darren M.
AU - Khanna, Shilpi
AU - Chalfant, Monica A.
AU - Saldanha, S. Adrian
AU - Hodder, Peter
AU - Tait, Bradley D.
AU - Garza, Dan
AU - Balch, William E.
AU - Morimoto, Richard I.
N1 - Funding Information:
We acknowledge J. Maddry, the SRI and the NINDS for support in performing the primary screen; P. Chase and P. Baillargeon of Scripps Florida for executing the SRIMSC screening activities; S. Fox, J. West, S. Westerheide, J. Moran, M. Beam and K. Orton for technical assistance; J.S. Pedersen for help developing the worm tracker system; and the Morimoto laboratory, in particular T. Gidalevitz, J. Kirstein, C. Voisine and A. Yu, for helpful comments. PC12 httQ74GFP cells were provided by D. Rubinsztein (University of Cambridge). Purified Hsp90β was a gift of A. Chadli (Georgia Health Science University). We thank A. Ciechanover for the rabbit polyclonal ubiquitin antibody (Israel Institute of Technology). The CFBE41oYFP cells were a gift from L. Galietta (Istituto Giannina Gaslini). This work was supported by the US National Institutes of Health (NIH) Training Grant in Signal Transduction and Cancer T32 CA70085 and the NIH Training Grant in Drug Discovery in Age Related Diseases T32 AG000260 (to B.C.), Portuguese PhD fellowship from the Fundação para a Ciência e Tecnologia (SFRH/BD/28461/2006) (to M.C.S.), NIH grants HL 079442, GM42336 and DK785483 (to W.E.B.), a fellowship from the Canadian Institutes for Health Research (CIHR) (to D.M.H.), the NIH Molecular Library Screening Center Network MH084512 (to F.M., S.A.S. and P.H.) and NIH grants GM038109, GM081192, AG026647 and NS047331 (to R.I.M.).
PY - 2012/2
Y1 - 2012/2
N2 - Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting this mechanism as a promising therapeutic approach. We describe the results of a screen comprised of ∼900,000 small molecules that identified new classes of small-molecule proteostasis regulators that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. These beneficial effects to proteome stability are mediated by HSF-1, FOXO, Nrf-2 and the chaperone machinery through mechanisms that are distinct from current known small-molecule activators of the heat shock response. We suggest that modulation of the proteostasis network by proteostasis regulators may be a promising therapeutic approach for the treatment of a variety of protein conformational diseases.
AB - Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting this mechanism as a promising therapeutic approach. We describe the results of a screen comprised of ∼900,000 small molecules that identified new classes of small-molecule proteostasis regulators that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. These beneficial effects to proteome stability are mediated by HSF-1, FOXO, Nrf-2 and the chaperone machinery through mechanisms that are distinct from current known small-molecule activators of the heat shock response. We suggest that modulation of the proteostasis network by proteostasis regulators may be a promising therapeutic approach for the treatment of a variety of protein conformational diseases.
UR - http://www.scopus.com/inward/record.url?scp=84856089134&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856089134&partnerID=8YFLogxK
U2 - 10.1038/nchembio.763
DO - 10.1038/nchembio.763
M3 - Article
C2 - 22198733
AN - SCOPUS:84856089134
VL - 8
SP - 185
EP - 196
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 2
ER -