Dataset Information

E3 Ubiquitin Ligase APC/C^Cdh1 Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination.

ABSTRACT: 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/C^Cdh1 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.

SUBMITTER: Kaushal K

PROVIDER: S-EPMC7699203 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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E3 Ubiquitin Ligase APC/C<sup>Cdh1</sup> Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination.

Kaushal Kamini K Woo Sang Hyeon SH Tyagi Apoorvi A Kim Dong Ha DH Suresh Bharathi B Kim Kye-Seong KS Ramakrishna Suresh S

International journal of molecular sciences 20201118 22

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 <i>FAH</i> 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 ...[more]

PMID: 33218190

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Project description:OBJECTIVES:Ubiquitin E3 ligase-mediated protein degradation regulates osteoblast function. Itch, an E3 ligase, affects numerous cell functions by regulating ubiquitination and proteasomal degradation of related proteins. However, the Itch-related cellular and molecular mechanisms by which osteoblast differentiation and function are elevated during bone fracture repair are as yet unknown. METHODS:We examined the expression levels of E3 ligases and NF-?B members in callus samples during bone fracture repair by quantitative polymerase chain reaction (qPCR) and the total amount of ubiquitinated proteins by Western blot analysis in wild-type (WT) mice. The expression levels of osteoblast-associated genes in fracture callus from Itch knockout (KO) mice and their WT littermates were examined by qPCR. The effect of NF-?B on Itch expression in C2C12 osteoblast cells was determined by a chromatin immunoprecipitation (ChIP) assay. RESULTS:The expression levels of WW Domain Containing E3 Ubiquitin Protein Ligase 1 (Wwp1), SMAD Specific E3 Ubiquitin Protein Ligase 1 (Smurf1), SMAD Specific E3 Ubiquitin Protein Ligase 2 (Smurf2) and Itch were all significantly increased in the fracture callus of WT mice, which was associated with elevated expression of NF-?B members and total ubiquitinated proteins. Callus tissue isolated from Itch KO mice expressed higher levels of osteoblast-associated genes, including Runx2, a positive regulator of osteoblast differentiation, but osteoclast-associated genes were not increased. Both NF-?B RelA and RelB proteins were found to bind to the NF-?B binding site in the mouse Itch promoter. CONCLUSIONS:Our findings indicate that Itch depletion may have a strong positive effect on osteoblast differentiation in fracture callus. Thus, ubiquitin E3 ligase Itch could be a potential target for enhancing bone fracture healing.Cite this article: J. Liu, X. Li, H. Zhang, R. Gu, Z. Wang, Z. Gao, L. Xing. Ubiquitin E3 ligase Itch negatively regulates osteoblast function by promoting proteasome degradation of osteogenic proteins. Bone Joint Res 2017;6:154-161. DOI: 10.1302/2046-3758.63.BJR-2016-0237.R1.

Dataset Information

E3 Ubiquitin Ligase APC/C^Cdh1 Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination.

Publications

E3 Ubiquitin Ligase APC/C<sup>Cdh1</sup> Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination.

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Dataset Information

E3 Ubiquitin Ligase APC/CCdh1 Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination.

Publications

E3 Ubiquitin Ligase APC/C<sup>Cdh1</sup> Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

E3 Ubiquitin Ligase APC/C^Cdh1 Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination.