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E3 ubiquitin ligase APC/CCdh1 regulation of phenylalanine hydroxylase stability and function

Title
E3 ubiquitin ligase APC/CCdh1 regulation of phenylalanine hydroxylase stability and function
Author
Ramakrishna Suresh
Keywords
enzyme assay; hyperphenylalaninemia; liver cancer; neurological damage; tetrahydrobiopterin; ubiquitin-proteasome system
Issue Date
2020-11
Publisher
MDPI
Citation
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, no. 23, article no. 9076
Abstract
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by the dysfunction of the enzyme phenylalanine hydroxylase (PAH). Alterations in the level of PAH leads to the toxic accumulation of phenylalanine in the blood and brain. Protein degradation mediated by ubiquitination is a principal cellular process for maintaining protein homeostasis. Therefore, it is important to identify the E3 ligases responsible for PAH turnover and proteostasis. Here, we report that anaphase-promoting complex/cyclosome-Cdh1 (APC/C)(Cdh1) is an E3 ubiquitin ligase complex that interacts and promotes the polyubiquitination of PAH through the 26S proteasomal pathway. Cdh1 destabilizes and declines the half-life of PAH. In contrast, the CRISPR/Cas9-mediated knockout of Cdh1 stabilizes PAH expression and enhances phenylalanine metabolism. Additionally, our current study demonstrates the clinical relevance of PAH and Cdh1 correlation in hepatocellular carcinoma (HCC). Overall, we show that PAH is a prognostic marker for HCC and Cdh1 could be a potential therapeutic target to regulate PAH-mediated physiological and metabolic disorders.
URI
https://www.mdpi.com/1422-0067/21/23/9076https://repository.hanyang.ac.kr/handle/20.500.11754/172158
ISSN
1422-0067
DOI
10.3390/ijms21239076
Appears in Collections:
GRADUATE SCHOOL OF BIOMEDICAL SCIENCE AND ENGINEERING[S](의생명공학전문대학원) > BIOMEDICAL SCIENCE(의생명과학과) > Articles
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