The Deubiquitinating Enzyme USP48 Interacts with the Retinal Degeneration-Associated Proteins UNC119a and ARL3

Sánchez-Bellver, Laura; Férriz-Gordillo, Andrea; Carrillo-Pz, Marc; Rabanal, Laura; Garcia-Gonzalo, Francesc R.; Marfany, Gemma

doi:10.3390/ijms232012527

Cited by 4 publications

(3 citation statements)

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“…Among USP7's many important targets are p53, PTEN, β-catenin, PLK1, and GLI transcription factors, to name a few (Zhou et al, 2015;Bhattacharya et al, 2018). After confirming that USP7 and EVC-EVC2 do indeed interact (Figure 2), we failed to detect any deubiquitinating activity of USP7 on the EVC-EVC2 complex, and the same was true for USP48, also involved in Hh signaling (Figure 3) (Zhou et al, 2017;Sanchez-Bellver et al, 2022). We also failed to see any effect of EVC knockout or overexpression on the USP7-GLI1 interaction (Supplementary Figure S1).…”

Section: Discussionmentioning

confidence: 82%

“…Besides USP7, we also tested the effect on EVC ubiquitination of USP48, another deubiquitinating enzyme known to regulate Hh signaling ( Zhou et al, 2017 ; Sanchez-Bellver et al, 2022 ). As with USP7, transfection with USP48 (WT or the C98S dominant negative) did not make any difference in the observed EVC-associated ubiquitination ( Figure 3B ).…”

Section: Resultsmentioning

confidence: 99%

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EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO

Barbeito,

Martin-Morales,

Palencia-Campos

et al. 2023

Front. Cell Dev. Biol.

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Ellis van Creveld syndrome and Weyers acrofacial dysostosis are two rare genetic diseases affecting skeletal development. They are both ciliopathies, as they are due to malfunction of primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae and are required for Hedgehog signaling, a key pathway during skeletal morphogenesis. These ciliopathies are caused by mutations affecting the EVC-EVC2 complex, a transmembrane protein heterodimer that regulates Hedgehog signaling from inside primary cilia. Despite the importance of this complex, the mechanisms underlying its stability, targeting and function are poorly understood. To address this, we characterized the endogenous EVC protein interactome in control and Evc-null cells. This proteomic screen confirmed EVC’s main known interactors (EVC2, IQCE, EFCAB7), while revealing new ones, including USP7, a deubiquitinating enzyme involved in Hedgehog signaling. We therefore looked at EVC-EVC2 complex ubiquitination. Such ubiquitination exists but is independent of USP7 (and of USP48, also involved in Hh signaling). We did find, however, that monoubiquitination of EVC-EVC2 cytosolic tails greatly reduces their protein levels. On the other hand, modification of EVC-EVC2 cytosolic tails with the small ubiquitin-related modifier SUMO3 has a different effect, enhancing complex accumulation at the EvC zone, immediately distal to the ciliary transition zone, possibly via increased binding to the EFCAB7-IQCE complex. Lastly, we find that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2’s Weyers-deleted peptide. Only one of these motifs had been characterized previously, so we have mapped the second herein. Altogether, our data shed light on EVC-EVC2 complex regulatory mechanisms, with implications for ciliopathies.

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Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO

Barbeito,

Martin-Morales,

Palencia-Campos

et al. 2023

Front. Cell Dev. Biol.

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“…Sánchez-Bellver et al [ 4 ] discuss the important role of the ubiquitin–proteasome system in the differentiation and ciliogenesis of photoreceptor cells. Mutations in the genes involved in ubiquitination and proteostasis can cause inherited retinal dystrophies (IRD) and ciliopathies.…”

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confidence: 99%

Regulation of Ubiquitin Family Signaling in Disease

Rosa

2023

IJMS

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Baicalin enhances proliferation and reduces inflammatory-oxidative stress effect in H2O2-induced granulosa cells apoptosis via USP48 protein regulation

Chen,

Lin,

Huang

et al. 2024

BMC Complement Med Ther

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Background Oxidative stress and inflammation can lead to apoptosis of ovarian granulosa cells (GCs), resulting in ovulation disorders and infertility. Baicalin (BAI) promotes cell proliferation and reduces inflammation and oxidative stress. However, the mechanisms by which BAI treatment affects oxidative stress and inflammation in GCs remain incompletely understood. Methods KGN cells were treated with hydrogen peroxide (H2O2) to analyze the effect of oxidative stress on GCs in vitro. Subsequently, H2O2-stimulated KGN cells were treated with BAI. The levels of GSH-Px, CAT, and SOD were measured using an activity assay kit. The levels of MDA, IL-1β, IL-6, IL-8, and TNF-α were measured by ELISA. Proliferation, apoptosis, and mRNA and protein levels were measured using the CCK8, flow cytometry, qRT-PCR, and western blotting. Results H2O2 treatment inhibited KGN cell proliferation and promoted apoptosis, accompanied by increased oxidative stress and inflammation. BAI promoted proliferation, inhibited apoptosis, and reduced oxidative stress and inflammation in H2O2-stimulated KGN cells. BAI treatment promoted USP48 protein expression, and USP48 knockdown abrogated the protective effects of BAI, indicating that USP48 is a downstream mediator of BAI. Conclusion BAI treatment enhanced cell proliferation and ameliorated oxidative stress and inflammation by enhancing USP48 protein expression. BAI, which is used clinically and as a dietary supplement, may alleviate oxidative stress-induced GC injury and ovarian disorders.

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The Deubiquitinating Enzyme USP48 Interacts with the Retinal Degeneration-Associated Proteins UNC119a and ARL3

Cited by 4 publications

References 74 publications

EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO

EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO

Regulation of Ubiquitin Family Signaling in Disease

Baicalin enhances proliferation and reduces inflammatory-oxidative stress effect in H2O2-induced granulosa cells apoptosis via USP48 protein regulation

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