Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70.
Missense mutant proteins, such as those produced in individuals with genetic diseases, are often misfolded and subject to processing by intracellular quality control systems. Previously, we have shown using a yeast system that enzymatic function could be restored to I278T cystathionine beta-synthase (CBS), a cause of homocystinuria, by treatments that affect the intracellular chaperone environment. Here, we extend these studies and show that it is possible to restore significant levels of enzyme activity to 17 of 18 (94%) disease causing missense mutations in human cystathionine beta-synthase (CBS) expressed in Saccharomyces cerevisiae by exposure to ethanol, proteasome inhibitors, or deletion of the Hsp26 small heat shock protein. All three of these treatments induce Hsp70, which is necessary but not sufficient for rescue. In addition to CBS, these same treatments can rescue disease-causing mutations in human p53 and the methylene tetrahydrofolate reductase gene. These findings do not appear restricted to S. cerevisiae, as proteasome inhibitors can restore significant CBS enzymatic activity to CBS alleles expressed in fibroblasts derived from homocystinuric patients and in a mouse model for homocystinuria that expresses human I278T CBS. These findings suggest that proteasome inhibitors and other Hsp70 inducing agents may be useful in the treatment of a variety of genetic diseases caused by missense mutations.
Singh
Laishram R
LR
Cancer Genetics and Signaling Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
Gupta
Sapna
S
Honig
Nicholaas H
NH
Kraus
Jan P
JP
Kruger
Warren D
WD
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002460:Cell Line; D002478:Cells, Cultured; D003541:Cystathionine beta-Synthase / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006712:Homocystinuria / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
D001897:Boronic Acids; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003541:Cystathionine beta-Synthase