E3 Ubiquitin Ligase APC/CCdh1 Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination
| Autor: | Dong Ha Kim, Kamini Kaushal, Suresh Ramakrishna, Bharathi Suresh, Sang Hyeon Woo, Kye Seong Kim, Apoorvi Tyagi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Catalysis
Inorganic Chemistry lcsh:Chemistry liver cancer Ubiquitin in silico analysis post-translational modifications Physical and Theoretical Chemistry Tyrosine Molecular Biology lcsh:QH301-705.5 Spectroscopy chemistry.chemical_classification biology Organic Chemistry Protein turnover General Medicine CRISPR/Cas9 knockout Computer Science Applications Amino acid Cell biology Ubiquitin ligase Enzyme chemistry Proteasome lcsh:Biology (General) lcsh:QD1-999 biology.protein Fumarylacetoacetate hydrolase ubiquitin-proteasome system |
| Zdroj: | International Journal of Molecular Sciences Volume 21 Issue 22 International Journal of Molecular Sciences, Vol 21, Iss 8719, p 8719 (2020) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms21228719 |
| Popis: | Fumarylacetoacetate hydrolase (FAH) is the last enzyme in the degradation pathway of the amino acids tyrosine and phenylalanine in mammals that catalyzes the hydrolysis of 4-fumarylacetoacetate into acetoacetate and fumarate. Mutations of the FAH gene are associated with hereditary tyrosinemia type I (HT1), resulting in reduced protein stability, misfolding, accelerated degradation and deficiency in functional proteins. Identifying E3 ligases, which are necessary for FAH protein stability and degradation, is essential. In this study, we demonstrated that the FAH protein level is elevated in liver cancer tissues compared to that in normal tissues. Further, we showed that the FAH protein undergoes 26S proteasomal degradation and its protein turnover is regulated by the anaphase-promoting complex/cyclosome-Cdh1 (APC/C)Cdh1 E3 ubiquitin ligase complex. APC/CCdh1 acts as a negative stabilizer of FAH protein by promoting FAH polyubiquitination and decreases the half-life of FAH protein. Thus, we envision that Cdh1 might be a key factor in the maintenance of FAH protein level to regulate FAH-mediated physiological functions. |
| Databáze: | OpenAIRE |
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