International Journal of Molecular Sciences

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3 pages, 187 KiB

Open AccessEditorial

Regulation of Ubiquitin Family Signaling in Disease

by Jose Luis Rosa

Int. J. Mol. Sci. 2023, 24(7), 6735; https://doi.org/10.3390/ijms24076735 - 4 Apr 2023

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Abstract

Ubiquitin is a small regulatory protein found in all eukaryotic cells [...] Full article

(This article belongs to the Special Issue Regulation of Ubiquitin Family Signaling in Disease)

Research

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20 pages, 3568 KiB

Open AccessArticle

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

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

Int. J. Mol. Sci. 2022, 23(20), 12527; https://doi.org/10.3390/ijms232012527 - 19 Oct 2022

Cited by 3 | Viewed by 2177

Abstract

Proteins related to the ubiquitin-proteasome system play an important role during the differentiation and ciliogenesis of photoreceptor cells. Mutations in several genes involved in ubiquitination and proteostasis have been identified as causative of inherited retinal dystrophies (IRDs) and ciliopathies. USP48 is a deubiquitinating [...] Read more.

Proteins related to the ubiquitin-proteasome system play an important role during the differentiation and ciliogenesis of photoreceptor cells. Mutations in several genes involved in ubiquitination and proteostasis have been identified as causative of inherited retinal dystrophies (IRDs) and ciliopathies. USP48 is a deubiquitinating enzyme whose role in the retina is still unexplored although previous studies indicate its relevance for neurosensory organs. In this work, we describe that a pool of endogenous USP48 localises to the basal body in retinal cells and provide data that supports the function of USP48 in the photoreceptor cilium. We also demonstrate that USP48 interacts with the IRD-associated proteins ARL3 and UNC119a, and stabilise their protein levels using different mechanisms. Our results suggest that USP48 may act in the regulation/stabilisation of key ciliary proteins for photoreceptor function, in the modulation of intracellular protein transport, and in ciliary trafficking to the photoreceptor outer segment. Full article

(This article belongs to the Special Issue Regulation of Ubiquitin Family Signaling in Disease)

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14 pages, 2302 KiB

Open AccessArticle

UDP-Glucose: A Cereblon-Dependent Glucokinase Protein Degrader

by Jaeyong Cho, Atsushi Miyagawa, Kazuki Yamaguchi, Wakana Abe, Yoji Tsugawa, Hatsuo Yamamura and Takeshi Imai

Int. J. Mol. Sci. 2022, 23(16), 9094; https://doi.org/10.3390/ijms23169094 - 13 Aug 2022

Cited by 4 | Viewed by 3540

Abstract

We previously reported that glucokinase is ubiquitinated and degraded by cereblon with an unknown endogenous glucokinase protein degrader. Here, we show that UDP-glucose is a glucokinase protein degrader. We identified that both glucose and UDP-glucose bind to glucokinase and that both uridine and [...] Read more.

We previously reported that glucokinase is ubiquitinated and degraded by cereblon with an unknown endogenous glucokinase protein degrader. Here, we show that UDP-glucose is a glucokinase protein degrader. We identified that both glucose and UDP-glucose bind to glucokinase and that both uridine and UDP-glucose bind to cereblon in a similar way to thalidomide. From these results, UDP-glucose was identified as a molecular glue between cereblon and glucokinase. Glucokinase produces glucose-6-phosphate in the pancreas and liver. Especially in β-cells, glucokinase is the main target of glucose for glucose-induced insulin secretion. UDP-glucose administration ubiquitinated and degraded glucokinase, lowered glucose-6-phosphate production, and then reduced insulin secretion in β-cell lines and mice. Maturity-onset diabetes of the young type 2 (MODY2) glucokinase^E256K mutant protein was resistant to UDP-glucose induced ubiquitination and degradation. Taken together, glucokinase ubiquitination and degradation signaling might be impaired in MODY2 patients. Full article

(This article belongs to the Special Issue Regulation of Ubiquitin Family Signaling in Disease)

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21 pages, 4471 KiB

Open AccessArticle

Membrane Targeting and GTPase Activity of Rab7 Are Required for Its Ubiquitination by RNF167

by Kim Ghilarducci, Valérie C. Cabana, Ali Harake, Laurent Cappadocia and Marc P. Lussier

Int. J. Mol. Sci. 2022, 23(14), 7847; https://doi.org/10.3390/ijms23147847 - 16 Jul 2022

Cited by 3 | Viewed by 2259

Abstract

Rab7 is a GTPase that controls late endosome and lysosome trafficking. Recent studies have demonstrated that Rab7 is ubiquitinated, a post-translational modification mediated by an enzymatic cascade. To date, only one ubiquitin E3 ligase and one deubiquitinase have been identified in regulating Rab7 [...] Read more.

Rab7 is a GTPase that controls late endosome and lysosome trafficking. Recent studies have demonstrated that Rab7 is ubiquitinated, a post-translational modification mediated by an enzymatic cascade. To date, only one ubiquitin E3 ligase and one deubiquitinase have been identified in regulating Rab7 ubiquitination. Here, we report that RNF167, a transmembrane endolysosomal ubiquitin ligase, can ubiquitinate Rab7. Using immunoprecipitation and in vitro ubiquitination assays, we demonstrate that Rab7 is a direct substrate of RNF167. Subcellular fractionation indicates that RNF167 activity maintains Rab7′s membrane localization. Epifluorescence microscopy in HeLa cells shows that Rab7-positive vesicles are larger under conditions enabling Rab7 ubiquitination by RNF167. Characterization of its ubiquitination reveals that Rab7 must be in its GTP-bound active form for membrane anchoring and, thus, accessible for RNF167-mediated ubiquitin attachment. Cellular distribution analyses of lysosome marker Lamp1 show that vesicle positioning is independent of Rab7 and RNF167 expression and that Rab7 endosomal localization is not affected by RNF167 knockdown. However, both Rab7 and RNF167 depletion affect each other’s lysosomal localization. Finally, this study demonstrates that the RNF167-mediated ubiquitination of Rab7 GTPase is impaired by variants of Charcot–Marie–Tooth Type 2B disease. This study identified RNF167 as a new ubiquitin ligase for Rab7 while expanding our knowledge of the mechanisms underlying the ubiquitination of Rab7. Full article

(This article belongs to the Special Issue Regulation of Ubiquitin Family Signaling in Disease)

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Review

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16 pages, 2041 KiB

Open AccessReview

Regulation of MAPK Signaling Pathways by the Large HERC Ubiquitin Ligases

by Joan Sala-Gaston, Laura Costa-Sastre, Leonardo Pedrazza, Arturo Martinez-Martinez, Francesc Ventura and Jose Luis Rosa

Int. J. Mol. Sci. 2023, 24(5), 4906; https://doi.org/10.3390/ijms24054906 - 3 Mar 2023

Cited by 3 | Viewed by 2177

Abstract

Protein ubiquitylation acts as a complex cell signaling mechanism since the formation of different mono- and polyubiquitin chains determines the substrate’s fate in the cell. E3 ligases define the specificity of this reaction by catalyzing the attachment of ubiquitin to the substrate protein. [...] Read more.

Protein ubiquitylation acts as a complex cell signaling mechanism since the formation of different mono- and polyubiquitin chains determines the substrate’s fate in the cell. E3 ligases define the specificity of this reaction by catalyzing the attachment of ubiquitin to the substrate protein. Thus, they represent an important regulatory component of this process. Large HERC ubiquitin ligases belong to the HECT E3 protein family and comprise HERC1 and HERC2 proteins. The physiological relevance of the Large HERCs is illustrated by their involvement in different pathologies, with a notable implication in cancer and neurological diseases. Understanding how cell signaling is altered in these different pathologies is important for uncovering novel therapeutic targets. To this end, this review summarizes the recent advances in how the Large HERCs regulate the MAPK signaling pathways. In addition, we emphasize the potential therapeutic strategies that could be followed to ameliorate the alterations in MAPK signaling caused by Large HERC deficiencies, focusing on the use of specific inhibitors and proteolysis-targeting chimeras. Full article

(This article belongs to the Special Issue Regulation of Ubiquitin Family Signaling in Disease)

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37 pages, 1622 KiB

Open AccessReview

Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders

by Hiroshi Kitamura

Int. J. Mol. Sci. 2023, 24(4), 3219; https://doi.org/10.3390/ijms24043219 - 6 Feb 2023

Cited by 15 | Viewed by 4972

Abstract

Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, and enzymatic activity. Ubiquitin-specific proteases (USPs) constitute the largest deubiquitinating enzyme family. To date, accumulating evidence indicates that several USPs positively and negatively affect metabolic diseases. [...] Read more.

Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, and enzymatic activity. Ubiquitin-specific proteases (USPs) constitute the largest deubiquitinating enzyme family. To date, accumulating evidence indicates that several USPs positively and negatively affect metabolic diseases. USP22 in pancreatic β-cells, USP2 in adipose tissue macrophages, USP9X, 20, and 33 in myocytes, USP4, 7, 10, and 18 in hepatocytes, and USP2 in hypothalamus improve hyperglycemia, whereas USP19 in adipocytes, USP21 in myocytes, and USP2, 14, and 20 in hepatocytes promote hyperglycemia. In contrast, USP1, 5, 9X, 14, 15, 22, 36, and 48 modulate the progression of diabetic nephropathy, neuropathy, and/or retinopathy. USP4, 10, and 18 in hepatocytes ameliorates non-alcoholic fatty liver disease (NAFLD), while hepatic USP2, 11, 14, 19, and 20 exacerbate it. The roles of USP7 and 22 in hepatic disorders are controversial. USP9X, 14, 17, and 20 in vascular cells are postulated to be determinants of atherosclerosis. Moreover, mutations in the Usp8 and Usp48 loci in pituitary tumors cause Cushing syndrome. This review summarizes the current knowledge about the modulatory roles of USPs in energy metabolic disorders. Full article

(This article belongs to the Special Issue Regulation of Ubiquitin Family Signaling in Disease)

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20 pages, 1497 KiB

Open AccessReview

NEDD4 E3 Ligases: Functions and Mechanisms in Bone and Tooth

by Ke Xu, Yanhao Chu, Qin Liu, Wenguo Fan, Hongwen He and Fang Huang

Int. J. Mol. Sci. 2022, 23(17), 9937; https://doi.org/10.3390/ijms23179937 - 1 Sep 2022

Cited by 4 | Viewed by 2374

Abstract

Protein ubiquitination is a precisely controlled enzymatic cascade reaction belonging to the post-translational modification of proteins. In this process, E3 ligases catalyze the binding of ubiquitin (Ub) to protein substrates and define specificity. The neuronally expressed developmentally down-regulated 4 (NEDD4) subfamily, belonging to [...] Read more.

Protein ubiquitination is a precisely controlled enzymatic cascade reaction belonging to the post-translational modification of proteins. In this process, E3 ligases catalyze the binding of ubiquitin (Ub) to protein substrates and define specificity. The neuronally expressed developmentally down-regulated 4 (NEDD4) subfamily, belonging to the homology to E6APC terminus (HECT) class of E3 ligases, has recently emerged as an essential determinant of multiple cellular processes in different tissues, including bone and tooth. Here, we place special emphasis on the regulatory role of the NEDD4 subfamily in the molecular and cell biology of osteogenesis. We elucidate in detail the specific roles, downstream substrates, and upstream regulatory mechanisms of the NEDD4 subfamily. Further, we provide an overview of the involvement of E3 ligases and deubiquitinases in the development, repair, and regeneration of another mineralized tissue—tooth. Full article

(This article belongs to the Special Issue Regulation of Ubiquitin Family Signaling in Disease)

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35 pages, 1631 KiB

Open AccessReview

Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases

by Nieves Lara-Ureña, Vahid Jafari and Mario García-Domínguez

Int. J. Mol. Sci. 2022, 23(14), 8012; https://doi.org/10.3390/ijms23148012 - 20 Jul 2022

Cited by 11 | Viewed by 3408

Abstract

SUMOylation is a post-translational modification that has emerged in recent decades as a mechanism involved in controlling diverse physiological processes and that is essential in vertebrates. The SUMO pathway is regulated by several enzymes, proteases and ligases being the main actors involved in [...] Read more.

SUMOylation is a post-translational modification that has emerged in recent decades as a mechanism involved in controlling diverse physiological processes and that is essential in vertebrates. The SUMO pathway is regulated by several enzymes, proteases and ligases being the main actors involved in the control of sumoylation of specific targets. Dysregulation of the expression, localization and function of these enzymes produces physiological changes that can lead to the appearance of different types of cancer, depending on the enzymes and target proteins involved. Among the most studied proteases and ligases, those of the SENP and PIAS families stand out, respectively. While the proteases involved in this pathway have specific SUMO activity, the ligases may have additional functions unrelated to sumoylation, which makes it more difficult to study their SUMO-associated role in cancer process. In this review we update the knowledge and advances in relation to the impact of dysregulation of SUMO proteases and ligases in cancer initiation and progression. Full article

(This article belongs to the Special Issue Regulation of Ubiquitin Family Signaling in Disease)

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