Abstract：
:Loss-of-function diseases are often caused by a mutation in a protein traversing the secretory pathway that compromises the normal balance between protein folding, trafficking, and degradation. We demonstrate that the innate cellular protein homeostasis, or proteostasis, capacity can be enhanced to fold mutated enzymes that would otherwise misfold and be degraded, using small molecule proteostasis regulators. Two proteostasis regulators are reported that alter the composition of the proteostasis network in the endoplasmic reticulum through the unfolded protein response, increasing the mutant folded protein concentration that can engage the trafficking machinery, restoring function to two nonhomologous mutant enzymes associated with distinct lysosomal storage diseases. Coapplication of a pharmacologic chaperone and a proteostasis regulator exhibits synergy because of the former's ability to further increase the concentration of trafficking-competent mutant folded enzymes. It may be possible to ameliorate loss-of-function diseases by using proteostasis regulators alone or in combination with a pharmacologic chaperone.
journal_name
Celljournal_title
Cellauthors
Mu TW,Ong DS,Wang YJ,Balch WE,Yates JR 3rd,Segatori L,Kelly JWdoi
10.1016/j.cell.2008.06.037subject
Has Abstractpub_date
2008-09-05 00:00:00pages
769-81issue
5eissn
0092-8674issn
1097-4172pii
S0092-8674(08)00824-6journal_volume
134pub_type
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