Atrophin–Rpd3 complex represses Hedgehog signaling by acting as a corepressor of CiR

Zhang, Zhao; Feng, Jing; Pan, Chenyu; Lv, Xiangdong; Wu, Wenqing; Zhou, Zhaocai; Liu, Feng; Zhang, Lei; Zhao, Yun

doi:10.1083/jcb.201306012

Cited by 38 publications

(44 citation statements)

References 43 publications

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“…In this screening, UbcD1 , also known as effete/eff , was identified as a negative regulator of Ci. Compared with control, Ci FL proteins accumulate, especially in the dorsal part of UbcD1 RNAi wing disks (Fig B and C), which is consistent with previous studies indicating that MS1096‐Gal4 has a higher transcriptional activity in the dorsal compartment compared with the ventral compartment . In response to Ci FL accumulation, the expression of dpp , one of the Hh target genes, was elevated as indicated by both real‐time qPCR analyses (Fig D) and dpp ‐LacZ staining (Fig E–F′), suggesting the up‐regulation of Hh signaling activity.…”

Section: Resultssupporting

confidence: 90%

UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing

Pan

Xia

et al. 2017

EMBO Reports

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The Hh pathway controls many morphogenetic processes in metazoans and plays important roles in numerous pathologies and in cancer. Hh signaling is mediated by the activity of the Gli/Ci family of transcription factors. Several studies in have shown that ubiquitination by the ubiquitin E3 ligases Slimb and Rdx(Hib) plays a crucial role in controlling Ci stability dependent on the levels of Hh signals. If Hh levels are low, Slimb adds K11- and K48-linked poly-ubiquitin chains on Ci resulting in partial degradation. Ubiquitin E2 enzymes are pivotal in determining the topologies of ubiquitin chains. However, which E2 enzymes participate in the selective ubiquitination-degradation of Ci remains elusive. Here, we find that the E2 enzyme UbcD1 negatively regulates Hh signaling activity in wing disks. Genetic and biochemical analyses in wing disks and in cultured cells reveal that UbcD1 directly controls Ci stability. Interestingly, UbcD1 is found to be selectively involved in Slimb-mediated Ci degradation. Finally, we show that the homologs of UbcD1 play a conserved role in modulating Hh signaling in vertebrates.

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Section: Resultssupporting

confidence: 90%

UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing

Pan

Xia

et al. 2017

EMBO Reports

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“…Through Co-IP experiments, we confirmed that zebrafish Usp7 (zUsp7) could bind zebrafish Gli proteins (zGli1, zGli2 and zGli3) (Figures S6A-C). Next, we examined the expression levels of several Hh-responsive genes, including patched2 ( ptch2 ), forkhead4 ( fkd4 ), NK2 homeobox 2b ( nkx2.2b ), and hedgehog interacting protein ( hhip ), in control or zusp7 morpholino treated zebrafish embryos 24h postfertilization (hpf) by in situ hybridization and real-time PCR (Zhang et al, 2013a). Compared with control morphants (Figures 7F, G, H, I), Hh target gene expression was notably down-regulated in zusp7 morphants (Figures 7F’, G’, H’, I’).…”

Section: Resultsmentioning

confidence: 99%

“…The in situ hybridization of zebrafish embryos were carried out based on the previously described protocol (Thisse and Thisse, 2008; Zhang et al, 2013a). In brief, zebrafish embryos were obtained by natural spawning of adult AB strain zebrafish.…”

Section: Methodsmentioning

confidence: 99%

Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling

Zhou

Xia

et al. 2015

Developmental Cell

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SUMMARY Hedgehog (Hh) signaling plays essential roles in animal development and tissue homeostasis, and its misregulation causes congenital diseases and cancers. Regulation of the ubiquitin/proteasome-mediated proteolysis of Ci/Gli transcription factors is central to Hh signaling, but whether deubiquitinase is involved in this process remains unknown. Here, we show that Hh stimulates the binding of an ubiquitin-specific protease Usp7 to Ci, which positively regulates Hh signaling activity through inhibiting Ci ubiquitination and degradation mediated by both Slimb-Cul1 and Hib-Cul3 E3 ligases. Furthermore, we find that Usp7 forms a complex with GMP-synthetase (GMPS) to promote Hh pathway activity. Finally, we show that the mammalian counterpart of Usp7, HAUSP, positively regulates Hh signaling by modulating Gli ubiquitination and stability. Our findings reveal a conserved mechanism by which Ci/Gli is stabilized by a deubiquitination enzyme and identify Usp7/HUASP as a critical regulator of Hh signaling and potential therapeutic target for Hh-related cancers.

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“…The combined activity of these kinases on GLI2/3 and Ci ultimately leads to binding of E3 SCF ubiquitin ligase and processing of GLI2 and GLI3 to their truncated repressor forms [8, 22, 26–32]. The mechanisms by which GLI proteins repress target genes is poorly understood, but includes histone deacetylation [33]. …”

Section: Processing Of Gli Proteins Into Transcriptional Repressorsmentioning

confidence: 99%

Transcriptional regulation of graded Hedgehog signaling

Falkenstein

Vokes

2014

Seminars in Cell & Developmental Biology

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The Hedgehog (Hh) pathway plays conserved roles in regulating a diverse spectrum of developmental processes. In some developmental contexts, a gradient of Hh protein specifies multiple cell types in a dose-dependent fashion, thereby acting as a morphogen. Hh signaling ultimately acts on the transcriptional level through GLI proteins. In the presence of Hh signaling full length GLI proteins act as transcriptional activators of target genes. Conversely, in the absence of Hh, GLI proteins act as transcriptional repressors. This review will highlight mechanisms contributing to how graded Hh signaling might translate to differential GLI activity and be interpreted into distinct transcriptional responses.

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Atrophin–Rpd3 complex represses Hedgehog signaling by acting as a corepressor of CiR

Abstract: Atrophin suppresses Hedgehog signaling by interacting with the transcriptional effector CiR and recruiting the histone deacetylase Rpd3 to the dpp locus to repress its transcription.

Cited by 38 publications

References 43 publications

UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing

UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing

Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling

Transcriptional regulation of graded Hedgehog signaling

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