E3 ubiquitin ligase Wwp1 regulates ciliary dynamics of the Hedgehog receptor Smoothened

Lv, Bo; Stuck, Michael W.; Desai, Paurav B.; Cabrera, Oscar A.; Pazour, Gregory J.

doi:10.1083/jcb.202010177

Cited by 29 publications

(26 citation statements)

References 87 publications

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“…It is possible that the vertebrates use additional E3 ligase(s) to prevent SMO activation, and/or the vertebrates use different mechanisms in different developmental tissues. It is possible that different E3 ligases are involved in different aspects of SMO regulation in a vertebrate system, exemplified by a recent study in which the E3 ubiquitin ligase WWP1 specifically promotes the ubiquitination and the ciliary dynamics of vertebrate SMO [58]. Further studies are expected to identify and characterize the E3 ligases in vertebrate systems, similar to those E3 ligases involved in Drosophila SMO regulation.…”

Section: Smo Ubiquitination Sumoylation and Stability Controlmentioning

confidence: 99%

Mechanisms of Smoothened Regulation in Hedgehog Signaling

Zhang

Liu

Jia

2021

Cells

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The seven-transmembrane protein, Smoothened (SMO), has shown to be critical for the hedgehog (HH) signal transduction on the cell membrane (and the cilium in vertebrates). SMO is subjected to multiple types of post-translational regulations, including phosphorylation, ubiquitination, and sumoylation, which alter SMO intracellular trafficking and cell surface accumulation. Recently, SMO is also shown to be regulated by small molecules, such as oxysterol, cholesterol, and phospholipid. The activity of SMO must be very well balanced by these different mechanisms in vivo because the malfunction of SMO will not only cause developmental defects in early stages, but also induce cancers in late stages. Here, we discuss the activation and inactivation of SMO by different mechanisms to better understand how SMO is regulated by the graded HH signaling activity that eventually governs distinct development outcomes.

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Section: Smo Ubiquitination Sumoylation and Stability Controlmentioning

confidence: 99%

Mechanisms of Smoothened Regulation in Hedgehog Signaling

Zhang

Liu

Jia

2021

Cells

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“…How mSmo sumoylation is stimulated by Hh and whether mSmo sumoylation also inhibits its ubiquitination remain to be explored. Although targeted expression of a UbK63-specific Dub could promote mSmo ciliary accumulation ( Shinde et al, 2020 ; Lv et al, 2021 ), whether Shh stimulates binding of a Dub(s) to antagonize mSmo ubiquitination remains to be determined. It is interesting to note that Hh stimulates the binding of PKA catalytic subunit (PKAc) to SmoCT in both Drosophila and mammalian systems ( Li et al, 2014 ; Ranieri et al, 2014 ; Arveseth et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Blocking of Smo ubiquitination by pharmacologically inhibiting E1 activity or by mutating two ubiquitin attachment sites in Smo resulted in Smo ciliary accumulation in the absence of Hh whereas fusing a ubiquitin moiety to Smo inhibited its ciliary accumulation in the presence of Hh ( Desai et al, 2020 ). Using CRISPR screen of candidate genes, a subsequent study by the same group identified the HECT domain E3 ligase Wwp1 as essential for Smo ubiquitination and ciliary exit ( Lv et al, 2021 ). Interestingly, Wwp1 is localized in primary cilia through its interaction with Ptc and Ptc-mediated ciliary localization of Wwp1 is critical for promoting Smo ubiquitination and ciliary exit ( Lv et al, 2021 ).…”

Section: Regulation Of Mammalian Smo Ciliary Trafficking and Abundanc...mentioning

confidence: 99%

“…Using CRISPR screen of candidate genes, a subsequent study by the same group identified the HECT domain E3 ligase Wwp1 as essential for Smo ubiquitination and ciliary exit ( Lv et al, 2021 ). Interestingly, Wwp1 is localized in primary cilia through its interaction with Ptc and Ptc-mediated ciliary localization of Wwp1 is critical for promoting Smo ubiquitination and ciliary exit ( Lv et al, 2021 ). Accordingly, Hh-induced ciliary exit of Ptc removes Wwp1 from the primary cilia, which may prevent Smo ubiquitination, leading to Smo ciliary accumulation ( Figure 2B ).…”

Section: Regulation Of Mammalian Smo Ciliary Trafficking and Abundanc...mentioning

confidence: 99%

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Regulation of Smoothened Trafficking and Abundance in Hedgehog Signaling

Jia

Jen

2022

Front. Cell Dev. Biol.

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The GPCR-family protein Smoothened (Smo) is essential for Hedgehog (Hh) signal transduction in both insects and vertebrates. The regulation of subcellular localization and abundance of Smo is a critical step in Hh signaling. Recent studies have demonstrated that Smo is subjected to ubiquitination mediated by multiple E3 ubiquitin ligases, leading to Smo endocytosis and subsequent degradation through the proteasome- and lysosome-mediated pathways in Drosophila. Ubiquitination of Smo also promotes its ciliary exit in mammalian cells. Hh inhibits Smo ubiquitination by blocking E3 ligase recruitment and promoting Smo deubiquitination through the ubiquitin-specific protease 8 (USP8) in Drosophila. Inhibition of Smo ubiquitination by Hh promotes Smo cell surface accumulation in Drosophila and ciliary accumulation in mammalian cells. Interestingly, Hh also induces sumoylation of Smo in both Drosophila and mammalian cells, which promotes Smo cell surface/ciliary accumulation. This review focuses on how ubiquitination and sumoylation regulate Smo intracellular trafficking and abundance and how these processes are regulated by Hh.

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“…At the basal state, the ubiquitin E3 ligase Wwp1 localizes to cilia by binding Ptch1. This promotes the ubiquitination of Smo, which promotes Smo’s interaction with the intraflagellar transport (IFT) system for removal from cilia (Desai et al, 2020; Lv et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Hedgehog Signaling Through Arih2-Mediated Smoothened Ubiquitination and Endoplasmic Reticulum-Associated Degradation

Zhang

Pazour

2022

Preprint

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During Hedgehog signaling, the ciliary levels of Ptch1 and Smo are regulated by pathway activity. At the basal state, Ptch1 localizes to cilia and prevents the ciliary accumulation and activation of Smo. Upon stimulation with Hedgehog ligand, Ptch1 exits cilia and relieves the inhibition of Smo. Uninhibited Smo concentrates in cilia, becomes activated, and activates the downstream steps of the pathway. Loss of the ubiquitin E3 ligase Arih2 elevates the cellular level of Smo, causes Smo to inappropriately localize to cilia at the at the basal state, and elevates basal expression of Hedgehog responsive genes. Mice express two isoforms of Arih2 with different N-termini, but neither isoform localizes to cilia. Instead, Arih2α is found in the nucleus and Arih2β is found on the cytoplasmic face of the endoplasmic reticulum. Re-expression of endoplasmic reticulum-localized Arih2β, but not nuclear-localized Arih2α returns the cellular Smo levels back to normal and rescues the ciliary Smo accumulation phenotype. When Arih2β is missing, protein aggregates accumulate in the endoplasmic reticulum and the unfolded protein response is activated. Inhibitor studies suggest that Arih2β functions to mark excess or misfolded Smo for degradation by endoplasmic reticulum-associated degradation. When Arih2β is defective, excess Smo, possibly misfolded, is delivered to the cell surface and cilium where it interferes with pathway regulation. These findings add another level of complexity to the Hedgehog pathway.

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E3 ubiquitin ligase Wwp1 regulates ciliary dynamics of the Hedgehog receptor Smoothened

Cited by 29 publications

References 87 publications

Mechanisms of Smoothened Regulation in Hedgehog Signaling

Mechanisms of Smoothened Regulation in Hedgehog Signaling

Regulation of Smoothened Trafficking and Abundance in Hedgehog Signaling

Regulation of Hedgehog Signaling Through Arih2-Mediated Smoothened Ubiquitination and Endoplasmic Reticulum-Associated Degradation

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