USP8 Promotes Smoothened Signaling by Preventing Its Ubiquitination and Changing Its Subcellular Localization

Xia, Ruohan; Jia, Hongge; Fan, Junping; Liu, Yajuan; Jia, Jianhang

doi:10.1371/journal.pbio.1001238

Cited by 121 publications

(202 citation statements)

References 50 publications

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“…One contributing factor to such defective EGFR trafficking is that USP8 controls the stability of ESCRT-0 components, Hrs and STAM in cells and in conditional knockout mice (185,219). However, for Frizzled receptor (Fz) and Smoothened (Smo), key components of Wingless (Wnt) and Hedgehog signaling pathways, respectively, USP8 plays a negative regulatory role with regard to receptor degradation more akin to that originally proposed for AMSH (153,180,281).…”

Section: B Escrt Dubsmentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

375

384

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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Section: B Escrt Dubsmentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

375

384

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“…SMO is regulated by the transmembrane protein Patched (PTC; Nakano et al, 1989), which acts as both an SMO antagonist and an HH coreceptor. Studies in flies show that in the absence of signal, PTC promotes SMO internalization and targeting to the lysosome for degradation (Fan et al, 2013;Li et al, 2012;Xia et al, 2012). These effects are blocked by HH, leading to accumulation of a hyperphosphorylated form of SMO at the plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused

et al. 2017

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Smoothened (SMO) is a G-protein-coupled receptor-related protein required for the transduction of Hedgehog (HH). The HH gradient leads to graded phosphorylation of SMO, mainly by the PKA and CKI kinases. How thresholds in HH morphogen regulate SMO to promote switch-like transcriptional responses is a central unsolved issue. Using the wing imaginal disc model in Drosophila, we identified new SMO phosphosites that enhance the effects of the PKA/CKI kinases on SMO accumulation, its localization at the plasma membrane and its activity. Surprisingly, phosphorylation at these sites is induced by the kinase Fused (FU), a known downstream effector of SMO. In turn, activation of SMO induces FU to act on its downstream targets. Overall, our data provide evidence for a SMO/FU positive regulatory loop nested within a multikinase phosphorylation cascade. We propose that this complex interplay amplifies signaling above a threshold that allows high HH signaling.

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“…The role of Ubpy in Drosophila development is equally controversial. It was suggested that the Hedgehog (Hh) signaling activator Smoothened (Smo) is subject to Ubpy control (Li et al, 2012;Xia et al, 2012). However, Mukai et al (Mukai et al, 2010) found that Smo abundance is unchanged when Ubpy is depleted.…”

Section: Introductionmentioning

confidence: 99%

“…Hrs mutants lacking the FYVE motif and PSAP domain, respectively, were generated by PCR. Wild-type (WT) and catalytically dead (CS) HA-Ubpy plasmids were gifts of Dr Jianhang Jia (Xia et al, 2012). Myc-Ub plasmid was provided by Dr Shunsuke Ishii (Dai et al, 2003).…”

mentioning

confidence: 99%

Ubpy controls the stability of the ESCRT-0 subunit Hrs in development

Zhang

Lei

et al. 2014

Development

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Ubiquitylated developmental membrane signaling proteins are often internalized for endocytic trafficking, through which endosomal sorting complexes required for transport (ESCRT) act sequentially to deliver internalized cargos to lysosomes. The ESCRT function in endocytic sorting is well established; however, it is not fully understood how the sorting machinery itself is regulated. Here, we show that Ubiquitin isopeptidase Y (Ubpy) plays a conserved role in vivo in the homeostasis of an essential ESCRT-0 complex component Hrs. We find that, in the absence of Drosophila Ubpy, multiple membrane proteins that are essential components of important signaling pathways accumulate in enlarged, aberrant endosomes. We further demonstrate that this phenotype results from endocytic pathway defects. We provide evidence that Ubpy interacts with and deubiquitylates Hrs. In Ubpy-null cells, Hrs becomes ubiquitylated and degraded in lysosomes, thus disrupting the integrity of ESCRT sorting machinery. Lastly, we find that signaling proteins are enriched in enlarged endosomes when Hrs activity is abolished. Together, our data support a model in which Ubpy plays a dual role in both cargo deubiquitylation and the ESCRT-0 stability during development. KEY WORDS: Developmental signaling, Endocytic machinery, ESCRT-0, Hrs, Ubpy, Drosophila INTRODUCTIONMany developmental signaling events are initiated through ligand binding to respective receptors at the plasma membrane. Following uptake into endocytic vesicles referred to as early or sorting endosomes, membrane receptors may recycle back to cell surface via tubular recycling endosomes. However, when directed by a ubiquitin (Ub) signal, receptor complexes are captured and sorted towards lysosomal degradation (Henne et al., 2011). The Ub moieties of protein cargos are recognized by ESCRT complexes, and are sorted into invaginating multivesicular bodies (MVBs). Mature MVBs fuse with lysosomes to deliver protein cargos for degradation (Raiborg and Stenmark, 2009). ESCRT-0 is composed of heterodimers of two subunits: Hrs and Stam. Both subunits bind Ub and clathrin, and Hrs additionally has an FYVE zinc-finger domain that binds phosphatidylinositol 3-phosphate. The ability to bind both lipid and Ub allows ESCRT-0 to initiate endosomal sorting (Clague et al., 2012).Ubpy (or USP8), a USP family deubiquitinase (DUB), participates in sorting of ubiquitylated receptors through its interaction with ESCRT-0 (Mizuno et al., 2005;Row et al., 2006). Most studies of Ubpy focus on endosomal trafficking of growth factor receptor tyrosine kinases (RTKs) in cultured vertebrate cells. However, conflicting data have been reported. In some cases, reduced Ubpy activity results in accumulation of ubiquitylated cargos (Bowers et al., 2006;Mizuno et al., 2006;Row et al., 2006; Alwan and van Leeuwen, 2007). Other studies suggest that Ubpy promotes RTK stability (Mizuno et al., 2005;Niendorf et al., 2007; Berlin et al., 2010). The role of Ubpy in Drosophila development is equally controversial. It was ...

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USP8 Promotes Smoothened Signaling by Preventing Its Ubiquitination and Changing Its Subcellular Localization

Abstract: Hedgehog regulates the activity of its signal transducer Smoothened by enhancing its interaction with the deubiquitinase USP8, thereby promoting Smoothened translocation to the cell surface and so enhancing Hh signaling.

Cited by 121 publications

References 50 publications

Deubiquitylases From Genes to Organism

Deubiquitylases From Genes to Organism

Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused

Ubpy controls the stability of the ESCRT-0 subunit Hrs in development

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