ArticlePLoS genetics2010
Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70.
Article in PLoS genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 58 citations in OpenAlex.
- Cellular turnover and degradation of the most common missense cystathionine beta-synthase variants causing homocystinuria.Protein science : a publication of the Protein Society · 2024Article
- Architecture and regulation of filamentous human cystathionine beta-synthase.Nature communications · 2024Article
- Proteostasis Modulation in Germline Missense von Hippel Lindau Disease.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria.British journal of pharmacology · 2023Review
- Genetic and Pharmacological Modulation of Cellular Proteostasis Leads to Partial Functional Rescue of Homocystinuria-Causing Cystathionine-Beta Synthase Variants.Molecular and cellular biology · 2023Article
- Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β-synthase in mice.PloS one · 2023Article
- How to fix a broken protein: restoring function to mutant human cystathionine β-synthase.Human genetics · 2022Review
- Selective functional inhibition of a tumor-derived p53 mutant by cytosolic chaperones identified using split-YFP in budding yeast.G3 (Bethesda, Md.) · 2021Article
- Chemical rescue of mutant proteins in living Saccharomyces cerevisiae cells by naturally occurring small molecules.G3 (Bethesda, Md.) · 2021Article
- Analysis of differential neonatal lethality in cystathionine β-synthase deficient mouse models using metabolic profiling.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Review
- Analysis of the Qatari R336C cystathionine β-synthase protein in mice.Journal of inherited metabolic disease · 2019Article
- In silico and in vivo models for Qatari-specific classical homocystinuria as basis for development of novel therapies.Human mutation · 2019Article
- Mouse modeling and structural analysis of the p.G307S mutation in human cystathionine β-synthase (The Journal of biological chemistry · 2018Article
- Cystathionine β-synthase deficiency: Of mice and men.Molecular genetics and metabolism · 2017Review
- The therapeutic potential of cystathionine β-synthetase/hydrogen sulfide inhibition in cancer.Antioxidants & redox signaling · 2015Review
- Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities.Journal of lipid research · 2014Review
- Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators.Journal of inherited metabolic disease · 2014Review
- Reduced response of Cystathionine Beta-Synthase (CBS) to S-Adenosylmethionine (SAM): Identification and functional analysis of CBS gene mutations in Homocystinuria patients.Journal of inherited metabolic disease · 2014Article
- Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.