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E3 ligase Herc4 regulates Hedgehog signalling through promoting Smoothened degradation.

ABSTRACT: Hedgehog (Hh) signalling plays conserved roles in controlling embryonic development; its dysregulation causes many diseases including cancers. The G protein-coupled receptor Smoothened (Smo) is the key signal transducer of the Hh pathway, whose posttranslational regulation has been shown to be critical for its accumulation and activation. Ubiquitination has been reported an essential posttranslational regulation of Smo. Here, we identify a novel E3 ligase of Smo, Herc4, which binds to Smo, and regulates Hh signalling by controlling Smo ubiquitination and degradation. Interestingly, our data suggest that Herc4-mediated Smo degradation is regulated by Hh in PKA-primed phosphorylation-dependent and independent manners.

SUBMITTER: Jiang W

PROVIDER: S-EPMC7261483 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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E3 ligase Herc4 regulates Hedgehog signalling through promoting Smoothened degradation.

Jiang Weirong W Yao Xia X Shan Zhaoliang Z Li Wenting W Gao Yuxue Y Zhang Qing Q

Journal of molecular cell biology 20190901 9

Hedgehog (Hh) signalling plays conserved roles in controlling embryonic development; its dysregulation causes many diseases including cancers. The G protein-coupled receptor Smoothened (Smo) is the key signal transducer of the Hh pathway, whose posttranslational regulation has been shown to be critical for its accumulation and activation. Ubiquitination has been reported an essential posttranslational regulation of Smo. Here, we identify a novel E3 ligase of Smo, Herc4, which binds to Smo, and r ...[more]

PMID: 30925584

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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 ligase Herc4 regulates Hedgehog signalling through promoting Smoothened degradation.

Publications

E3 ligase Herc4 regulates Hedgehog signalling through promoting Smoothened degradation.

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