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

Zhou, Zizhang; Xia, Yao; Li, Shuang; Xiong, Yue; Dong, Xiaohua; Zhao, Yun; Jen, Jin; Zhang, Qing

doi:10.1016/j.devcel.2015.05.016

Cited by 77 publications

(83 citation statements)

References 63 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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“…In this reaction, glutamine acts as an amido-N donor and is converted into glutamate. Studies in Drosophila and human cells found that GMPS associates with the nuclear ubiquitinspecific protease 7 (USP7) (van der Knaap et al 2005Knaap et al , 2010Sarkari et al 2009;Reddy et al 2014;Zhou et al 2015). GMPS activates USP7 through an allosteric mechanism, which is independent of its GMP synthesis function (van der Knaap et al 2005Knaap et al , 2010Faesen et al 2011).…”

Section: Chromatin and Transcription Control By Nucleotide Biosynthetmentioning

confidence: 99%

“…Depending on the strength of the hedgehog signal, Ci can either be degraded, form a truncated transcriptional repressor, or act as a full-length activator. Zhou et al (2015) showed that GMPS-USP7 is a positive mediator of hedgehog signaling through deubiquitylation and stabilization of the active form of Ci.…”

Section: Chromatin and Transcription Control By Nucleotide Biosynthetmentioning

confidence: 99%

Undercover: gene control by metabolites and metabolic enzymes

2016

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To make the appropriate developmental decisions or maintain homeostasis, cells and organisms must coordinate the expression of their genome and metabolic state. However, the molecular mechanisms that relay environmental cues such as nutrient availability to the appropriate gene expression response remain poorly understood. There is a growing awareness that central components of intermediary metabolism are cofactors or cosubstrates of chromatin-modifying enzymes. As such, their concentrations constitute a potential regulatory interface between the metabolic and chromatin states. In addition, there is increasing evidence for a direct involvement of classic metabolic enzymes in gene expression control. These dual-function proteins may provide a direct link between metabolic programing and the control of gene expression. Here, we discuss our current understanding of the molecular mechanisms connecting metabolism to gene expression and their implications for development and disease.Metabolism and gene regulation are two fundamental biological processes that are essential to all living organisms. Homeostasis, cell growth, and differentiation all require the coordination of metabolic state and gene expression programs. Nevertheless, how expression of the genome adapts to metabolic state or environmental changes is not well understood. One level of regulation involves signal transduction pathways that control key transcription factors that act as master regulators of gene expression programs. In addition, post-translational modifications (PTMs) of chromatin play a major role in the activation or repression of gene transcription. These include acetylation, methylation, and phosphorylation of the histones and DNA methylation. Some of these chromatin modifications are involved in the maintenance of stable patterns of gene expression, usually referred to as epigenetic regulation. Pertinently, the activity of enzymes that modulate chromatin is critically dependent on central metabolites as cofactors or cosubstrates. Thus, the availability of metabolites that are required for the activity of histone-modifying enzymes may connect metabolism to chromatin structure and gene expression. Finally, selective metabolic enzymes act in the nucleus to adjust gene transcription in response to changes in metabolic state. Here, we review the interface between metabolism and gene transcription. We focus on the molecular mechanisms involved and discuss unresolved issues and implications for development and disease. The basics of metabolism and gene expression controlMetabolism is the total of all chemical reactions in cells and organisms that maintain life. Metabolism can be divided into two classes: catabolic processes (the breakdown of molecules that usually results in the release of energy) and anabolic processes (the synthesis of components such as proteins, lipids, and nucleic acids, which costs energy). Cellular (or intermediary) metabolism is organized in separate chemical pathways formed by a chain of linked enzymatic reactions in wh...

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“…A recent report has identified USP7 as a DUB that is able to stabilise Gli-proteins, by opposing several Ubiquitin–E3-ligase complexes [Cullin1 (Slimb/βTRCP), Cullin3 (HIB/SPOP) and the HECT E3-ligase ITCH] that are involved in Gli protein processing or degradation in the absence and presence of Hh, respectively (Zhou et al, 2015). Our results suggest a more complex scenario in which the restricted localisation of USP21 facilitates the accumulation of an inactive pool of Gli1 at the centrosome.…”

Section: Discussionmentioning

confidence: 99%

“…USP8 has been associated with this cascade in Drosophila , where it promotes recycling of SMO (Clague et al, 2012b; Li et al, 2012; Xia et al, 2012). However, the role of DUBs in the mammalian Hh-signaling pathway has only recently been explored (Zhou et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

The centrosomal deubiquitylase USP21 regulates Gli1 transcriptional activity and stability

Heride

Rigden

Bertsoulaki

et al. 2016

Journal of Cell Science

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USP21 is a centrosome-associated deubiquitylase (DUB) that has been implicated in the formation of primary cilia – crucial organelles for the regulation of the Hedgehog (Hh) signaling pathway in vertebrates. Here, we identify KCTD6 – a cullin-3 E3-ligase substrate adapter that has been previously linked to Hh signaling – as well as Gli1, the key transcription factor responsible for Hh signal amplification, as new interacting partners of USP21. We identify a cryptic structured protein interaction domain in KCTD6, which is predicted to have a similar fold to Smr domains. Importantly, we show that both depletion and overexpression of catalytically active USP21 suppress Gli1-dependent transcription. Gli proteins are negatively regulated through protein kinase A (PKA)-dependent phosphorylation. We provide evidence that USP21 recruits and stabilises Gli1 at the centrosome where it promotes its phosphorylation by PKA. By revealing an intriguing functional pairing between a spatially restricted deubiquitylase and a kinase, our study highlights the centrosome as an important hub for signal coordination.

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

Cited by 77 publications

References 63 publications

UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing

UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing

Undercover: gene control by metabolites and metabolic enzymes

The centrosomal deubiquitylase USP21 regulates Gli1 transcriptional activity and stability

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