The deubiquitinase UCHL5/UCH37 positively regulates Hedgehog signaling by deubiquitinating Smoothened

Zhou, Zizhang; Xia, Yao; Pang, Shu; Chen, Ping; Jiang, Weirong; Shan, Z.P.; Zhang, Qing

doi:10.1093/jmcb/mjx036

Cited by 47 publications

(34 citation statements)

References 57 publications

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“…Less is known about the role of Ub in regulating the dynamics of Ptch1 and Smo, although previous studies support a function for Ub in this process. In Drosophila, Smo is ubiquitinated in the off state, and this drives sequestration in cytoplasmic vesicles (Ma et al, 2016;Xia et al, 2012;Zhou et al, 2018). The E3 ligase modifying Drosophila Smo is reported to be Herc4 (Jiang et al, 2019;Sun et al, 2019), and other studies suggest that the Usp8 and Uchl5 deubiquitinases regulate cellular localization of Smo.…”

Section: Discussionmentioning

confidence: 99%

“…Uchl5 stabilizes Drosophila Smo and promotes its localization on the cell surface. The human homologue UCH37 was reported to promote Smo localization to cilia (Zhou et al, 2018). However, we used CRISPR to knock out Herc4 along with its close paralog Herc3, Usp8, and Uchl5/ (1) is ubiquitinated by unknown E3 ligase (2) on lysine residues in intracellular loop three, making it cargo for removal from the cilium by the IFT system (3).…”

Section: Discussionmentioning

confidence: 99%

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Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling

Desai

Stuck

et al. 2020

Journal of Cell Biology

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In the absence of Hedgehog ligand, patched-1 (Ptch1) localizes to cilia and prevents ciliary accumulation and activation of smoothened (Smo). Upon ligand binding, Ptch1 is removed from cilia, and Smo is derepressed and accumulates in cilia where it activates signaling. The mechanisms regulating these dynamic movements are not well understood, but defects in intraflagellar transport components, including Ift27 and the BBSome, cause Smo to accumulate in cilia without pathway activation. We find that in the absence of ligand-induced pathway activation, Smo is ubiquitinated and removed from cilia, and this process is dependent on Ift27 and BBSome components. Activation of Hedgehog signaling decreases Smo ubiquitination and ciliary removal, resulting in its accumulation. Blocking ubiquitination of Smo by an E1 ligase inhibitor or by mutating two lysine residues in intracellular loop three causes Smo to aberrantly accumulate in cilia without pathway activation. These data provide a mechanism to control Smo’s ciliary level during Hedgehog signaling by regulating the ubiquitination state of the receptor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling

Desai

Stuck

et al. 2020

Journal of Cell Biology

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“…UCHL3 enhanced the DNA damage repair mediated by radiotherapy and chemotherapy in cancer cells via binding to tyrosyl DNA phosphodiesterase 1 (TDP1), a chromosome breakage repair related enzyme, and mediating TDP1 deubiquitination [32][33][34]. UCHL5 could stabilize the seven-pass transmembrane receptor Smoothened (Smo) protein via deubiquitination and further activated the Hedgehog (Hh) signaling pathway to maintain tissue homeostasis of cancers [35]. Beyond that, dephosphorylation of Smad2 could also be mediated by UCHL5, which plays a crucial role in suppressing cell apoptosis and sustaining cell survival [36].…”

Section: Biological Effects Of Shdraic On Gc Cellsmentioning

confidence: 99%

LncRNA DRAIC inhibits proliferation and metastasis of gastric cancer cells through interfering with NFRKB deubiquitination mediated by UCHL5

Zhang

Kuang

et al. 2020

Cell Mol Biol Lett

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Background: Long non-coding RNA (lncRNA) as a widespread and pivotal epigenetic molecule participates in the occurrence and progression of malignant tumors. DRAIC, a kind of lncRNA whose coding gene location is on 15q23 chromatin, has been found to be weakly expressed in a variety of malignant tumors and acts as a suppressor, but its characteristics and role in gastric cancer (GC) remain to be elucidated. Methods: Sixty-seven primary GC tissues and paired paracancerous normal tissues were collected. Bioinformatics is used to predict the interaction molecules of DRAIC. DRAIC and NFRKB were overexpressed or interfered exogenously in GC cells by lentivirus or transient transfection. Quantitative real-time PCR (qPCR) and western blotting were used to evaluate the expression of DRAIC, UCHL5 and NFRKB. The combinations of DRAIC and NFRKB or UCHL5 and NFRKB were verified by RNA-IP and Co-IP assays. Ubiquitination-IP and the treatment of MG132 and CHX were used to detect the ubiquitylation level of NFRKB. The CCK-8 and transwell invasion and migration assays measured the proliferation, migration and invasion of GC cells. Results: DRAIC is down-regulated in GC tissues and cell lines while its potential interacting molecules UCHL5 and NFRKB are up-regulated, and DRAIC is positively correlated with NFRKB protein instead of mRNA. Lower DRAIC and higher UCHL5 and NFRKB indicated advanced progression of GC patients. DRAIC could increase NFRKB protein significantly instead of NFRKB mRNA and UCHL5, and bind to UCHL5. DRAIC combined with UCHL5 and attenuated binding of UCHL5 and NFRKB, meanwhile promoting the degradation of NFRKB via ubiquitination, and then inhibited the proliferation and metastasis of GC cells, which can be rescued by oeNFRKB. Conclusion: DRAIC suppresses GC proliferation and metastasis via interfering with the combination of UCHL5 and NFRKB and mediating ubiquitination degradation.

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“…UCHL5 is involved in the activation of the Wnt, Hedgehog and transforming growth factor-β (TGF-β) signaling pathways. UCHL5 regulates gene transcription and DNA damage repair and replication [7][8][9][10][11].…”

Section: Ivyspringmentioning

confidence: 99%

Deubiquitinase UCHL5 is elevated and associated with a poor clinical outcome in lung adenocarcinoma (LUAD)

Zhang

Yang

et al. 2020

J. Cancer

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Lung cancer is one of the most common malignant tumors in the world, with a high rate of malignancy and mortality. Seeking new biomarkers and potential drug targets is urgent for effective treatment of the disease. Deubiquitinase UCHL5/UCH37, as an important component of the 26S proteasome, plays critical roles in ubiquitinated substrate degradation. Although previous studies have shown that UCHL5 promotes tumorigenesis, its role in lung cancer remains largely unknown. In this study, we evaluated the expression and clinical significance of UCHL5 in non-small cell lung cancer (NSCLC). The results demonstrated that the UCHL5 expression level was significantly upregulated in NSCLC tissues compared with the adjacent noncancerous tissues. The level of UCHL5 was associated with tumor size, lymph node invasion, TNM stage and malignant tumor history in patients with lung adenocarcinoma (LUAD). Importantly, high UCHL5 expression predicted a poor overall survival (OS) and a poor disease-free survival (DFS) in patients with LUAD. Univariate regression analysis showed that tumor size, lymph node invasion, TNM stage and UCHL5 expression were associated with OS and DFS in patients with LUAD. The multivariate analysis indicated that the UCHL5 expression level was an independent prognostic factor for OS (HR=1.171, 95% CI=1.052-1.303) and DFS (HR=1.143, 95% CI=1.031-1.267) in these patients. UCHL5 knockdown in LUAD cells significantly inhibited cell proliferation and reduced the expression of key cell cycle proteins. These findings indicate that UCHL5 may serve as a potential prognostic marker and a new therapeutic target for patients with LUAD.

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The deubiquitinase UCHL5/UCH37 positively regulates Hedgehog signaling by deubiquitinating Smoothened

Cited by 47 publications

References 57 publications

Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling

Ubiquitin links smoothened to intraflagellar transport to regulate Hedgehog signaling

LncRNA DRAIC inhibits proliferation and metastasis of gastric cancer cells through interfering with NFRKB deubiquitination mediated by UCHL5

Deubiquitinase UCHL5 is elevated and associated with a poor clinical outcome in lung adenocarcinoma (LUAD)

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