International Journal of Molecular Sciences

Research

Jump to: Review

16 pages, 4039 KiB

Open AccessArticle

Deubiquitinating Enzyme USP12 Regulates the Pro-Apoptosis Protein Bax

by Hae-Seul Choi, Eun-Su Lim and Kwang-Hyun Baek

Int. J. Mol. Sci. 2022, 23(21), 13107; https://doi.org/10.3390/ijms232113107 - 28 Oct 2022

Cited by 8 | Viewed by 2269

Abstract

The Bax protein is a pro-apoptotic protein belonging to the Bcl-2 family, involved in inducing apoptosis at the mitochondrial level. Regulating the protein levels of Bax is essential to enhancing apoptosis. In the current study, we ascertained the presence of deubiquitinating enzymes (DUBs) [...] Read more.

The Bax protein is a pro-apoptotic protein belonging to the Bcl-2 family, involved in inducing apoptosis at the mitochondrial level. Regulating the protein levels of Bax is essential to enhancing apoptosis. In the current study, we ascertained the presence of deubiquitinating enzymes (DUBs) associated with Bax by performing the yeast two-hybrid screening (Y2H). We determined that ubiquitin-specific protease 12 (USP12), one of the DUBs, is associated with Bax. The binding of USP12 to Bax shows the interaction as a DUB, which regulates ubiquitination on Bax. Taken together, we believe that USP12 regulates Bax by detaching ubiquitin on K63-linked chains, indicating that USP12 affects the cellular functions of Bax, but it is not related with proteasomal degradation. The half-life of the Bax protein was determined by performing the site-directed mutagenesis of putative ubiquitination sites on Bax (K128R, K189R, and K190R). Of these, Bax (K128R and K190R) showed less ubiquitination; therefore, we compared the half-life of Bax (WT) and Bax K mutant forms in vitro. Interestingly, Bax (K189R) showed a higher ubiquitination level and shorter half-life than Bax (WT), and the (K128R and K190R) mutant form has a longer half-life than Bax (WT). Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

11 pages, 4320 KiB

Open AccessArticle

Overexpression of UBA5 in Cells Mimics the Phenotype of Cells Lacking UBA5

by Sujata Kumari, Sayanika Banerjee, Manoj Kumar, Arata Hayashi, Balakrishnan Solaimuthu, Einav Cohen-Kfir, Yoav D. Shaul, Alexander Rouvinski and Reuven Wiener

Int. J. Mol. Sci. 2022, 23(13), 7445; https://doi.org/10.3390/ijms23137445 - 4 Jul 2022

Cited by 3 | Viewed by 2872

Abstract

Ufmylation is a posttranslational modification in which the modifier UFM1 is attached to target proteins. This conjugation requires the concerted work of three enzymes named UBA5, UFC1, and UFL1. Initially, UBA5 activates UFM1 in a process that ends with UFM1 attached to UBA5’s [...] Read more.

Ufmylation is a posttranslational modification in which the modifier UFM1 is attached to target proteins. This conjugation requires the concerted work of three enzymes named UBA5, UFC1, and UFL1. Initially, UBA5 activates UFM1 in a process that ends with UFM1 attached to UBA5’s active site Cys. Then, in a trans-thiolation reaction, UFM1 is transferred from UBA5 to UFC1, forming a thioester bond with the latter. Finally, with the help of UFL1, UFM1 is transferred to the final destination—a lysine residue on a target protein. Therefore, not surprisingly, deletion of one of these enzymes abrogates the conjugation process. However, how overexpression of these enzymes affects this process is not yet clear. Here we found, unexpectedly, that overexpression of UBA5, but not UFC1, damages the ability of cells to migrate, in a similar way to cells lacking UBA5 or UFC1. At the mechanistic level, we found that overexpression of UBA5 reverses the trans-thiolation reaction, thereby leading to a back transfer of UFM1 from UFC1 to UBA5. This, as seen in cells lacking UBA5, reduces the level of charged UFC1 and therefore harms the conjugation process. In contrast, co-expression of UBA5 with UFM1 abolishes this effect, suggesting that the reverse transfer of UFM1 from UFC1 to UBA5 depends on the level of free UFM1. Overall, our results propose that the cellular expression level of the UFM1 conjugation enzymes has to be tightly regulated to ensure the proper directionality of UFM1 transfer. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Graphical abstract

14 pages, 4932 KiB

Open AccessArticle

USP37 Deubiquitinates CDC73 in HPT-JT Syndrome

by Su Yeon Kim, Ji-young Lee, Yun-jung Cho, Kwan Hoon Jo, Eun Sook Kim, Je Ho Han, Kwang-Hyun Baek and Sung-dae Moon

Int. J. Mol. Sci. 2022, 23(12), 6364; https://doi.org/10.3390/ijms23126364 - 7 Jun 2022

Cited by 3 | Viewed by 2447

Abstract

The CDC73/HRPT2 gene, a defect which causes hyperparathyroidism–jaw tumor (HPT-JT) syndrome, encodes CDC73/parafibromin. We aimed to investigate whether CDC73 would be a target for ubiquitin–proteasome degradation. We cloned full-length cDNAs encoding a family of 58 ubiquitin-specific deubiquitinating enzymes (DUBs), also known as ubiquitin-specific [...] Read more.

The CDC73/HRPT2 gene, a defect which causes hyperparathyroidism–jaw tumor (HPT-JT) syndrome, encodes CDC73/parafibromin. We aimed to investigate whether CDC73 would be a target for ubiquitin–proteasome degradation. We cloned full-length cDNAs encoding a family of 58 ubiquitin-specific deubiquitinating enzymes (DUBs), also known as ubiquitin-specific proteases (USPs). Use of the yeast two-hybrid system then enabled us to identify USP37 as interacting with CDC73. The biochemical interaction between the USP37 and CDC73 and their reciprocal binding domains were studied. Co-localization of CDC73 and USP37 was observed in cells. CDC73 was found to be polyubiquitinated, and polyubiquitination of CDC73 was prominent in mutants. CDC73 was deubiquitinated via K48-specific ubiquitin chains by USP37, but not by the catalytically inactive USP37^C350S mutant. Observation of the binding between deletion mutants of CDC73 and USP37 revealed that the β-catenin binding site of CDC73 and the ubiquitin-interacting motifs 2 and 3 (UIM2 and 3) of USP37 were responsible for the interaction between the two proteins. Moreover, these two enzymes co-existed within the nucleus of COS7 cells. We conclude that USP37 is a DUB for CDC73 and that the two proteins interact through specific domains, suggesting that USP37 is responsible for the stability of CDC73 in HPT-JT syndrome. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Graphical abstract

15 pages, 3193 KiB

Open AccessArticle

The Deubiquitinase OTUB1 Is a Key Regulator of Energy Metabolism

by Amalia Ruiz-Serrano, Christina N. Boyle, Josep M. Monné Rodríguez, Julia Günter, Agnieszka E. Jucht, Svende Pfundstein, Andreas M. Bapst, Thomas A. Lutz, Roland H. Wenger and Carsten C. Scholz

Int. J. Mol. Sci. 2022, 23(3), 1536; https://doi.org/10.3390/ijms23031536 - 28 Jan 2022

Cited by 5 | Viewed by 4356

Abstract

Dysregulated energy metabolism is a major contributor to a multitude of pathologies, including obesity and diabetes. Understanding the regulation of metabolic homeostasis is of utmost importance for the identification of therapeutic targets for the treatment of metabolically driven diseases. We previously identified the [...] Read more.

Dysregulated energy metabolism is a major contributor to a multitude of pathologies, including obesity and diabetes. Understanding the regulation of metabolic homeostasis is of utmost importance for the identification of therapeutic targets for the treatment of metabolically driven diseases. We previously identified the deubiquitinase OTUB1 as substrate for the cellular oxygen sensor factor-inhibiting HIF (FIH) with regulatory effects on cellular energy metabolism, but the physiological relevance of OTUB1 is unclear. Here, we report that the induced global deletion of OTUB1 in adult mice (Otub1 iKO) elevated energy expenditure, reduced age-dependent body weight gain, facilitated blood glucose clearance and lowered basal plasma insulin levels. The respiratory exchange ratio was maintained, indicating an unaltered nutrient oxidation. In addition, Otub1 deletion in cells enhanced AKT activity, leading to a larger cell size, higher ATP levels and reduced AMPK phosphorylation. AKT is an integral part of insulin-mediated signaling and Otub1 iKO mice presented with increased AKT phosphorylation following acute insulin administration combined with insulin hypersensitivity. We conclude that OTUB1 is an important regulator of metabolic homeostasis. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

13 pages, 4759 KiB

Open AccessArticle

TARBP2 Suppresses Ubiquitin-Proteasomal Degradation of HIF-1α in Breast Cancer

by Jie-Ning Li, Pai-Sheng Chen, Ching-Feng Chiu, Yu-Jhen Lyu, Chiao Lo, Li-Wei Tsai and Ming-Yang Wang

Int. J. Mol. Sci. 2022, 23(1), 208; https://doi.org/10.3390/ijms23010208 - 24 Dec 2021

Cited by 8 | Viewed by 3327

Abstract

TAR (HIV-1) RNA binding protein 2 (TARBP2) is an RNA-binding protein participating in cytoplasmic microRNA processing. Emerging evidence has shown the oncogenic role of TARBP2 in promoting cancer progression, making it an unfavorable prognosis marker for breast cancer. Hypoxia is a hallmark of [...] Read more.

TAR (HIV-1) RNA binding protein 2 (TARBP2) is an RNA-binding protein participating in cytoplasmic microRNA processing. Emerging evidence has shown the oncogenic role of TARBP2 in promoting cancer progression, making it an unfavorable prognosis marker for breast cancer. Hypoxia is a hallmark of the tumor microenvironment which induces hypoxia-inducible factor-1α (HIF-1α) for transcriptional regulation. HIF-1α is prone to be rapidly destabilized by the ubiquitination–proteasomal degradation system. In this study, we found that TARBP2 expression is significantly correlated with induced hypoxia signatures in human breast cancer tissues. At a cellular level, HIF-1α protein level was maintained by TARBP2 under either normoxia or hypoxia. Mechanistically, TARBP2 enhanced HIF-1α protein stability through preventing its proteasomal degradation. In addition, downregulation of multiple E3 ligases targeting HIF-1α (VHL, FBXW7, TRAF6) and reduced ubiquitination of HIF-1α were also induced by TARBP2. In support of our clinical findings that TARBP2 is correlated with tumor hypoxia, our IHC staining showed the positive correlation between HIF-1α and TARBP2 in human breast cancer tissues. Taken together, this study indicates the regulatory role of TARBP2 in the ubiquitination–proteasomal degradation of HIF-1α protein in breast cancer. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

13 pages, 2161 KiB

Open AccessArticle

Lucanthone, Autophagy Inhibitor, Enhances the Apoptotic Effects of TRAIL through miR-216a-5p-Mediated DR5 Upregulation and DUB3-Mediated Mcl-1 Downregulation

by Ji Yun Yoon, Seon Min Woo, Seung Un Seo, So Rae Song, Seul Gi Lee and Taeg Kyu Kwon

Int. J. Mol. Sci. 2022, 23(1), 17; https://doi.org/10.3390/ijms23010017 - 21 Dec 2021

Cited by 4 | Viewed by 2324

Abstract

A lucanthone, one of the family of thioxanthenones, has been reported for its inhibitory effects of apurinic endonuclease-1 and autophagy. In this study, we investigated whether lucanthone could enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in various cancer cells. Combined treatment with [...] Read more.

A lucanthone, one of the family of thioxanthenones, has been reported for its inhibitory effects of apurinic endonuclease-1 and autophagy. In this study, we investigated whether lucanthone could enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in various cancer cells. Combined treatment with lucanthone and TRAIL significantly induced apoptosis in human renal carcinoma (Caki and ACHN), prostate carcinoma (PC3), and lung carcinoma (A549) cells. However, combined treatment did not induce apoptosis in normal mouse kidney cells (TCMK-1) and normal human skin fibroblast (HSF). Lucanthone downregulated protein expression of deubiquitinase DUB3, and a decreased expression level of DUB3 markedly led to enhance TRAIL-induced apoptosis. Ectopic expression of DUB3 inhibited combined treatment with lucanthone and TRAIL-induced apoptosis. Moreover, lucanthone increased expression level of DR5 mRNA via downregulation of miR-216a-5p. Transfection of miR-216a-5p mimics suppressed the lucanthone-induced DR5 upregulation. Taken together, these results provide the first evidence that lucanthone enhances TRAIL-induced apoptosis through DR5 upregulation by downregulation of miR-216a-5p and DUB3-dependent Mcl-1 downregulation in human renal carcinoma cells. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

14 pages, 1546 KiB

Open AccessArticle

Regulation of O-Linked N-Acetyl Glucosamine Transferase (OGT) through E6 Stimulation of the Ubiquitin Ligase Activity of E6AP

by Kangli Peng, Ruochuan Liu, Caiwei Jia, Yiyang Wang, Geon H. Jeong, Li Zhou, Ronggui Hu, Hiroaki Kiyokawa, Jun Yin and Bo Zhao

Int. J. Mol. Sci. 2021, 22(19), 10286; https://doi.org/10.3390/ijms221910286 - 24 Sep 2021

Cited by 15 | Viewed by 2993

Abstract

Glycosyltransferase OGT catalyzes the conjugation of O-linked β-D-N-acetylglucosamine (O-GlcNAc) to Ser and Thr residues of the cellular proteins and regulates many key processes in the cell. Here, we report the identification of OGT as a ubiquitination target of HECT-type E3 ubiquitin (UB) ligase [...] Read more.

Glycosyltransferase OGT catalyzes the conjugation of O-linked β-D-N-acetylglucosamine (O-GlcNAc) to Ser and Thr residues of the cellular proteins and regulates many key processes in the cell. Here, we report the identification of OGT as a ubiquitination target of HECT-type E3 ubiquitin (UB) ligase E6AP, whose overexpression in HEK293 cells would induce the degradation of OGT. We also found that the expression of E6AP in HeLa cells with the endogenous expression of the E6 protein of the human papillomavirus (HPV) would accelerate OGT degradation by the proteasome and suppress O-GlcNAc modification of OGT substrates in the cell. Overall, our study establishes a new mechanism of OGT regulation by the ubiquitin–proteasome system (UPS) that mediates the crosstalk between protein ubiquitination and O-GlcNAcylation pathways underlying diverse cellular processes. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

21 pages, 5012 KiB

Open AccessArticle

ATG101 Degradation by HUWE1-Mediated Ubiquitination Impairs Autophagy and Reduces Survival in Cancer Cells

by JaeYung Lee, Jiyea Kim, Jeongeun Shin, YongHyun Kang, Jungwon Choi and Heesun Cheong

Int. J. Mol. Sci. 2021, 22(17), 9182; https://doi.org/10.3390/ijms22179182 - 25 Aug 2021

Cited by 8 | Viewed by 3749

Abstract

Autophagy is a critical cytoprotective mechanism against stress, which is initiated by the protein kinase Unc-51-like kinase 1 (ULK1) complex. Autophagy plays a role in both inhibiting the progression of diseases and facilitating pathogenesis, so it is critical to elucidate the mechanisms regulating [...] Read more.

Autophagy is a critical cytoprotective mechanism against stress, which is initiated by the protein kinase Unc-51-like kinase 1 (ULK1) complex. Autophagy plays a role in both inhibiting the progression of diseases and facilitating pathogenesis, so it is critical to elucidate the mechanisms regulating individual components of the autophagy machinery under various conditions. Here, we examined whether ULK1 complex component autophagy-related protein 101 (ATG101) is downregulated via ubiquitination, and whether this in turn suppresses autophagy activity in cancer cells. Knockout of ATG101 in cancer cells using CRISPR resulted in severe growth retardation and lower survival under nutrient starvation. Transfection of mutant ATG101 revealed that the C-terminal region is a key domain of ubiquitination, while co-immunoprecipitation and knockdown experiments revealed that HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1(HUWE1) is a major E3 ubiquitin ligase targeting ATG101. Protein levels of ATG101 was more stable and the related-autophagy activity was higher in HUWE1-depleted cancer cells compared to wild type (WT) controls, indicating that HUWE1-mediated ubiquitination promotes ATG101 degradation. Moreover, enhanced autophagy in HUWE1-depleted cancer cells was reversed by siRNA-mediated ATG101 knockdown. Stable ATG101 level in HUWE1-depleted cells was a strong driver of autophagosome formation similar to upregulation of the known HUWE1 substrate WD repeat domain, phosphoinositide interacting 2 (WIPI2). Cellular survival rates were higher in HUWE1-knockdown cancer cells compared to controls, while concomitant siRNA-mediated ATG101 knockdown tends to increase apoptosis rate. Collectively, these results suggest that HUWE1 normally serves to suppress autophagy by ubiquitinating and triggering degradation of ATG101 and WIPI2, which in turn represses the survival of cancer cells. Accordingly, ATG101-mediated autophagy may play a critical role in overcoming metabolic stress, thereby contributing to the growth, survival, and treatment resistance of certain cancers. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

20 pages, 9920 KiB

Open AccessArticle

TRIM25 and DEAD-Box RNA Helicase DDX3X Cooperate to Regulate RIG-I-Mediated Antiviral Immunity

by Sarah C. Atkinson, Steven M. Heaton, Michelle D. Audsley, Oded Kleifeld and Natalie A. Borg

Int. J. Mol. Sci. 2021, 22(16), 9094; https://doi.org/10.3390/ijms22169094 - 23 Aug 2021

Cited by 12 | Viewed by 4108

Abstract

The cytoplasmic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiate interferon (IFN) production and antiviral gene expression in response to RNA virus infection. Consequently, RLR signalling is tightly regulated by both host and viral factors. Tripartite motif protein 25 (TRIM25) is an E3 ligase [...] Read more.

The cytoplasmic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiate interferon (IFN) production and antiviral gene expression in response to RNA virus infection. Consequently, RLR signalling is tightly regulated by both host and viral factors. Tripartite motif protein 25 (TRIM25) is an E3 ligase that ubiquitinates multiple substrates within the RLR signalling cascade, playing both ubiquitination-dependent and -independent roles in RIG-I-mediated IFN induction. However, additional regulatory roles are emerging. Here, we show a novel interaction between TRIM25 and another protein in the RLR pathway that is essential for type I IFN induction, DEAD-box helicase 3X (DDX3X). In vitro assays and knockdown studies reveal that TRIM25 ubiquitinates DDX3X at lysine 55 (K55) and that TRIM25 and DDX3X cooperatively enhance IFNB1 induction following RIG-I activation, but the latter is independent of TRIM25’s catalytic activity. Furthermore, we found that the influenza A virus non-structural protein 1 (NS1) disrupts the TRIM25:DDX3X interaction, abrogating both TRIM25-mediated ubiquitination of DDX3X and cooperative activation of the IFNB1 promoter. Thus, our results reveal a new interplay between two RLR-host proteins that cooperatively enhance IFN-β production. We also uncover a new and further mechanism by which influenza A virus NS1 suppresses host antiviral defence. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

Review

Jump to: Research

16 pages, 3226 KiB

Open AccessReview

Targeting Deubiquitinating Enzymes (DUBs) That Regulate Mitophagy via Direct or Indirect Interaction with Parkin

by Eliona Tsefou and Robin Ketteler

Int. J. Mol. Sci. 2022, 23(20), 12105; https://doi.org/10.3390/ijms232012105 - 11 Oct 2022

Cited by 4 | Viewed by 3628

Abstract

The quality control of mitochondria is critical for the survival of cells, and defects in the pathways required for this quality control can lead to severe disease. A key quality control mechanism in cells is mitophagy, which functions to remove damaged mitochondria under [...] Read more.

The quality control of mitochondria is critical for the survival of cells, and defects in the pathways required for this quality control can lead to severe disease. A key quality control mechanism in cells is mitophagy, which functions to remove damaged mitochondria under conditions of various stresses. Defective mitophagy can lead to a number of diseases including neurodegeneration. It has been proposed that an enhancement of mitophagy can improve cell survival, enhance neuronal function in neurodegeneration and extend health and lifespans. In this review, we highlight the role of deubiquitinating enzymes (DUBs) in the regulation of mitophagy. We summarise the current knowledge on DUBs that regulate mitophagy as drug targets and provide a list of small molecule inhibitors that are valuable tools for the further development of therapeutic strategies targeting the mitophagy pathway in neurodegeneration. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

23 pages, 1645 KiB

Open AccessReview

Ubiquitin Ligases in Longevity and Aging Skeletal Muscle

by David C. Hughes, Leslie M. Baehr, David S. Waddell, Adam P. Sharples and Sue C. Bodine

Int. J. Mol. Sci. 2022, 23(14), 7602; https://doi.org/10.3390/ijms23147602 - 9 Jul 2022

Cited by 15 | Viewed by 5333

Abstract

The development and prevalence of diseases associated with aging presents a global health burden on society. One hallmark of aging is the loss of proteostasis which is caused in part by alterations to the ubiquitin–proteasome system (UPS) and lysosome–autophagy system leading to impaired [...] Read more.

The development and prevalence of diseases associated with aging presents a global health burden on society. One hallmark of aging is the loss of proteostasis which is caused in part by alterations to the ubiquitin–proteasome system (UPS) and lysosome–autophagy system leading to impaired function and maintenance of mass in tissues such as skeletal muscle. In the instance of skeletal muscle, the impairment of function occurs early in the aging process and is dependent on proteostatic mechanisms. The UPS plays a pivotal role in degradation of misfolded and aggregated proteins. For the purpose of this review, we will discuss the role of the UPS system in the context of age-related loss of muscle mass and function. We highlight the significant role that E3 ubiquitin ligases play in the turnover of key components (e.g., mitochondria and neuromuscular junction) essential to skeletal muscle function and the influence of aging. In addition, we will briefly discuss the contribution of the UPS system to lifespan. By understanding the UPS system as part of the proteostasis network in age-related diseases and disorders such as sarcopenia, new discoveries can be made and new interventions can be developed which will preserve muscle function and maintain quality of life with advancing age. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

12 pages, 1975 KiB

Open AccessReview

SAGA-Dependent Histone H2Bub1 Deubiquitination Is Essential for Cellular Ubiquitin Balance during Embryonic Development

by Farrah El-Saafin, Didier Devys, Steven A. Johnsen, Stéphane D. Vincent and László Tora

Int. J. Mol. Sci. 2022, 23(13), 7459; https://doi.org/10.3390/ijms23137459 - 5 Jul 2022

Cited by 8 | Viewed by 3298

Abstract

Ubiquitin (ub) is a small, highly conserved protein widely expressed in eukaryotic cells. Ubiquitination is a post-translational modification catalyzed by enzymes that activate, conjugate, and ligate ub to proteins. Substrates can be modified either by addition of a single ubiquitin molecule (monoubiquitination), or [...] Read more.

Ubiquitin (ub) is a small, highly conserved protein widely expressed in eukaryotic cells. Ubiquitination is a post-translational modification catalyzed by enzymes that activate, conjugate, and ligate ub to proteins. Substrates can be modified either by addition of a single ubiquitin molecule (monoubiquitination), or by conjugation of several ubs (polyubiquitination). Monoubiquitination acts as a signaling mark to control diverse biological processes. The cellular and spatial distribution of ub is determined by the opposing activities of ub ligase enzymes, and deubiquitinases (DUBs), which remove ub from proteins to generate free ub. In mammalian cells, 1–2% of total histone H2B is monoubiquitinated. The SAGA (Spt Ada Gcn5 Acetyl-transferase) is a transcriptional coactivator and its DUB module removes ub from H2Bub1. The mammalian SAGA DUB module has four subunits, ATXN7, ATXN7L3, USP22, and ENY2. Atxn7l3^−/− mouse embryos, lacking DUB activity, have a five-fold increase in H2Bub1 retention, and die at mid-gestation. Interestingly, embryos lacking the ub encoding gene, Ubc, have a similar phenotype. Here we provide a current overview of data suggesting that H2Bub1 retention on the chromatin in Atxn7l3^−/− embryos may lead to an imbalance in free ub distribution. Thus, we speculate that ATXN7L3-containing DUBs impact the free cellular ub pool during development. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

18 pages, 2050 KiB

Open AccessReview

Monoubiquitination in Homeostasis and Cancer

by Yujie Chen, Dandan Zhou, Yinan Yao, Yutong Sun, Fan Yao and Li Ma

Int. J. Mol. Sci. 2022, 23(11), 5925; https://doi.org/10.3390/ijms23115925 - 25 May 2022

Cited by 15 | Viewed by 5646

Abstract

Monoubiquitination is a post-translational modification (PTM), through which a single ubiquitin molecule is covalently conjugated to a lysine residue of the target protein. Monoubiquitination regulates the activity, subcellular localization, protein–protein interactions, or endocytosis of the substrate. In doing so, monoubiquitination is implicated in [...] Read more.

Monoubiquitination is a post-translational modification (PTM), through which a single ubiquitin molecule is covalently conjugated to a lysine residue of the target protein. Monoubiquitination regulates the activity, subcellular localization, protein–protein interactions, or endocytosis of the substrate. In doing so, monoubiquitination is implicated in diverse cellular processes, including gene transcription, endocytosis, signal transduction, cell death, and DNA damage repair, which in turn regulate cell-cycle progression, survival, proliferation, and stress response. In this review, we summarize the functions of monoubiquitination and discuss how this PTM modulates homeostasis and cancer. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

26 pages, 3904 KiB

Open AccessReview

Structural and Functional Insights into GID/CTLH E3 Ligase Complexes

by Matthew E. R. Maitland, Gilles A. Lajoie, Gary S. Shaw and Caroline Schild-Poulter

Int. J. Mol. Sci. 2022, 23(11), 5863; https://doi.org/10.3390/ijms23115863 - 24 May 2022

Cited by 17 | Viewed by 5017

Abstract

Multi-subunit E3 ligases facilitate ubiquitin transfer by coordinating various substrate receptor subunits with a single catalytic center. Small molecules inducing targeted protein degradation have exploited such complexes, proving successful as therapeutics against previously undruggable targets. The C-terminal to LisH (CTLH) complex, also called [...] Read more.

Multi-subunit E3 ligases facilitate ubiquitin transfer by coordinating various substrate receptor subunits with a single catalytic center. Small molecules inducing targeted protein degradation have exploited such complexes, proving successful as therapeutics against previously undruggable targets. The C-terminal to LisH (CTLH) complex, also called the glucose-induced degradation deficient (GID) complex, is a multi-subunit E3 ligase complex highly conserved from Saccharomyces cerevisiae to humans, with roles in fundamental pathways controlling homeostasis and development in several species. However, we are only beginning to understand its mechanistic basis. Here, we review the literature of the CTLH complex from all organisms and place previous findings on individual subunits into context with recent breakthroughs on its structure and function. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

15 pages, 1013 KiB

Open AccessReview

The Roles of Ubiquitination in Pathogenesis of Influenza Virus Infection

by Eun-Sook Park, Mehrangiz Dezhbord, Ah Ram Lee and Kyun-Hwan Kim

Int. J. Mol. Sci. 2022, 23(9), 4593; https://doi.org/10.3390/ijms23094593 - 21 Apr 2022

Cited by 14 | Viewed by 4295

Abstract

The ubiquitin system denotes a potent post-translational modification machinery that is capable of activation or deactivation of target proteins through reversible linkage of a single ubiquitin or ubiquitin chains. Ubiquitination regulates major cellular functions such as protein degradation, trafficking and signaling pathways, innate [...] Read more.

The ubiquitin system denotes a potent post-translational modification machinery that is capable of activation or deactivation of target proteins through reversible linkage of a single ubiquitin or ubiquitin chains. Ubiquitination regulates major cellular functions such as protein degradation, trafficking and signaling pathways, innate immune response, antiviral defense, and virus replication. The RNA sensor RIG-I ubiquitination is specifically induced by influenza A virus (IAV) to activate type I IFN production. Influenza virus modulates the activity of major antiviral proteins in the host cell to complete its full life cycle. Its structural and non-structural proteins, matrix proteins and the polymerase complex can regulate host immunity and antiviral response. The polymerase PB1-F2 of mutated 1918 IAV, adapts a novel IFN antagonist function by sending the DDX3 into proteasomal degradation. Ultimately the fate of virus is determined by the outcome of interplay between viral components and host antiviral proteins and ubiquitination has a central role in the encounter of virus and its host cell. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

15 pages, 1682 KiB

Open AccessReview

The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration

by Shanez Haouari, Patrick Vourc’h, Médéric Jeanne, Sylviane Marouillat, Charlotte Veyrat-Durebex, Débora Lanznaster, Frédéric Laumonnier, Philippe Corcia, Hélène Blasco and Christian R. Andres

Int. J. Mol. Sci. 2022, 23(7), 3882; https://doi.org/10.3390/ijms23073882 - 31 Mar 2022

Cited by 11 | Viewed by 3577

Abstract

The ubiquitin pathway regulates the function of many proteins and controls cellular protein homeostasis. In recent years, it has attracted great interest in neurodevelopmental and neurodegenerative diseases. Here, we have presented the first review on the roles of the 9 proteins of the [...] Read more.

The ubiquitin pathway regulates the function of many proteins and controls cellular protein homeostasis. In recent years, it has attracted great interest in neurodevelopmental and neurodegenerative diseases. Here, we have presented the first review on the roles of the 9 proteins of the HECT E3 ligase NEDD4 subfamily in the development and function of neurons in the central nervous system (CNS). We discussed their regulation and their direct or indirect involvement in neurodevelopmental diseases, such as intellectual disability, and neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease or Amyotrophic Lateral Sclerosis. Further studies on the roles of these proteins, their regulation and their targets in neurons will certainly contribute to a better understanding of neuronal function and dysfunction, and will also provide interesting information for the development of therapeutics targeting them. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

22 pages, 2343 KiB

Open AccessReview

Atypical Ubiquitination and Parkinson’s Disease

by Olga Buneeva and Alexei Medvedev

Int. J. Mol. Sci. 2022, 23(7), 3705; https://doi.org/10.3390/ijms23073705 - 28 Mar 2022

Cited by 26 | Viewed by 5743

Abstract

Ubiquitination (the covalent attachment of ubiquitin molecules to target proteins) is one of the main post-translational modifications of proteins. Historically, the type of polyubiquitination, which involves K48 lysine residues of the monomeric ubiquitin, was the first studied type of ubiquitination. It usually targets [...] Read more.

Ubiquitination (the covalent attachment of ubiquitin molecules to target proteins) is one of the main post-translational modifications of proteins. Historically, the type of polyubiquitination, which involves K48 lysine residues of the monomeric ubiquitin, was the first studied type of ubiquitination. It usually targets proteins for their subsequent proteasomal degradation. All the other types of ubiquitination, including monoubiquitination; multi-monoubiquitination; and polyubiquitination involving lysine residues K6, K11, K27, K29, K33, and K63 and N-terminal methionine, were defined as atypical ubiquitination (AU). Good evidence now exists that AUs, participating in the regulation of various cellular processes, are crucial for the development of Parkinson’s disease (PD). These AUs target various proteins involved in PD pathogenesis. The K6-, K27-, K29-, and K33-linked polyubiquitination of alpha-synuclein, the main component of Lewy bodies, and DJ-1 (another PD-associated protein) is involved in the formation of insoluble aggregates. Multifunctional protein kinase LRRK2 essential for PD is subjected to K63- and K27-linked ubiquitination. Mitophagy mediated by the ubiquitin ligase parkin is accompanied by K63-linked autoubiquitination of parkin itself and monoubiquitination and polyubiquitination of mitochondrial proteins with the formation of both classical K48-linked ubiquitin chains and atypical K6-, K11-, K27-, and K63-linked polyubiquitin chains. The ubiquitin-specific proteases USP30, USP33, USP8, and USP15, removing predominantly K6-, K11-, and K63-linked ubiquitin conjugates, antagonize parkin-mediated mitophagy. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

14 pages, 797 KiB

Open AccessReview

Role of the Ubiquitin System in Stress Granule Metabolism

by Nazife Tolay and Alexander Buchberger

Int. J. Mol. Sci. 2022, 23(7), 3624; https://doi.org/10.3390/ijms23073624 - 26 Mar 2022

Cited by 10 | Viewed by 4571

Abstract

Eukaryotic cells react to various stress conditions with the rapid formation of membrane-less organelles called stress granules (SGs). SGs form by multivalent interactions between RNAs and RNA-binding proteins and are believed to protect stalled translation initiation complexes from stress-induced degradation. SGs contain hundreds [...] Read more.

Eukaryotic cells react to various stress conditions with the rapid formation of membrane-less organelles called stress granules (SGs). SGs form by multivalent interactions between RNAs and RNA-binding proteins and are believed to protect stalled translation initiation complexes from stress-induced degradation. SGs contain hundreds of different mRNAs and proteins, and their assembly and disassembly are tightly controlled by post-translational modifications. The ubiquitin system, which mediates the covalent modification of target proteins with the small protein ubiquitin (‘ubiquitylation’), has been implicated in different aspects of SG metabolism, but specific functions in SG turnover have only recently emerged. Here, we summarize the evidence for the presence of ubiquitylated proteins at SGs, review the functions of different components of the ubiquitin system in SG formation and clearance, and discuss the link between perturbed SG clearance and the pathogenesis of neurodegenerative disorders. We conclude that the ubiquitin system plays an important, medically relevant role in SG biology. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

25 pages, 1927 KiB

Open AccessReview

Acute Myeloid Leukemia-Related Proteins Modified by Ubiquitin and Ubiquitin-like Proteins

by Sang-Soo Park and Kwang-Hyun Baek

Int. J. Mol. Sci. 2022, 23(1), 514; https://doi.org/10.3390/ijms23010514 - 3 Jan 2022

Cited by 4 | Viewed by 4149

Abstract

Acute myeloid leukemia (AML), the most common form of an acute leukemia, is a malignant disorder of stem cell precursors of the myeloid lineage. Ubiquitination is one of the post-translational modifications (PTMs), and the ubiquitin-like proteins (Ubls; SUMO, NEDD8, and ISG15) play a [...] Read more.

Acute myeloid leukemia (AML), the most common form of an acute leukemia, is a malignant disorder of stem cell precursors of the myeloid lineage. Ubiquitination is one of the post-translational modifications (PTMs), and the ubiquitin-like proteins (Ubls; SUMO, NEDD8, and ISG15) play a critical role in various cellular processes, including autophagy, cell-cycle control, DNA repair, signal transduction, and transcription. Also, the importance of Ubls in AML is increasing, with the growing research defining the effect of Ubls in AML. Numerous studies have actively reported that AML-related mutated proteins are linked to Ub and Ubls. The current review discusses the roles of proteins associated with protein ubiquitination, modifications by Ubls in AML, and substrates that can be applied for therapeutic targets in AML. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

21 pages, 1601 KiB

Open AccessReview

Modulation of Ubiquitin Signaling in Innate Immune Response by Herpesviruses

by Sandrine-M. Soh, Yeong-Jun Kim, Hong-Hee Kim and Hye-Ra Lee

Int. J. Mol. Sci. 2022, 23(1), 492; https://doi.org/10.3390/ijms23010492 - 1 Jan 2022

Cited by 9 | Viewed by 3557

Abstract

The ubiquitin proteasome system (UPS) is a protein degradation machinery that is crucial for cellular homeostasis in eukaryotes. Therefore, it is not surprising that the UPS coordinates almost all host cellular processes, including host–pathogen interactions. This protein degradation machinery acts predominantly by tagging [...] Read more.

The ubiquitin proteasome system (UPS) is a protein degradation machinery that is crucial for cellular homeostasis in eukaryotes. Therefore, it is not surprising that the UPS coordinates almost all host cellular processes, including host–pathogen interactions. This protein degradation machinery acts predominantly by tagging substrate proteins designated for degradation with a ubiquitin molecule. These ubiquitin tags have been involved at various steps of the innate immune response. Hence, herpesviruses have evolved ways to antagonize the host defense mechanisms by targeting UPS components such as ubiquitin E3 ligases and deubiquitinases (DUBs) that establish a productive infection. This review delineates how herpesviruses usurp the critical roles of ubiquitin E3 ligases and DUBs in innate immune response to escape host-antiviral immune response, with particular focus on retinoic acid-inducible gene I (RIG-I)-like receptors (RLR), cyclic-GMP-AMP (cGAMP) synthase (cGAS), stimulator of interferon (IFN) genes (STING) pathways, and inflammasome signaling. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

21 pages, 1548 KiB

Open AccessReview

Regulation of Hedgehog Signal Transduction by Ubiquitination and Deubiquitination

by Qing Zhang and Jin Jiang

Int. J. Mol. Sci. 2021, 22(24), 13338; https://doi.org/10.3390/ijms222413338 - 11 Dec 2021

Cited by 10 | Viewed by 3770

Abstract

The Hedgehog (Hh) family of secreted proteins governs embryonic development and adult tissue homeostasis in species ranging from insects to mammals. Deregulation of Hh pathway activity has been implicated in a wide range of human disorders, including congenital diseases and cancer. Hh exerts [...] Read more.

The Hedgehog (Hh) family of secreted proteins governs embryonic development and adult tissue homeostasis in species ranging from insects to mammals. Deregulation of Hh pathway activity has been implicated in a wide range of human disorders, including congenital diseases and cancer. Hh exerts its biological influence through a conserved signaling pathway. Binding of Hh to its receptor Patched (Ptc), a twelve-span transmembrane protein, leads to activation of an atypical GPCR family protein and Hh signal transducer Smoothened (Smo), which then signals downstream to activate the latent Cubitus interruptus (Ci)/Gli family of transcription factors. Hh signal transduction is regulated by ubiquitination and deubiquitination at multiple steps along the pathway including regulation of Ptc, Smo and Ci/Gli proteins. Here we review the effect of ubiquitination and deubiquitination on the function of individual Hh pathway components, the E3 ubiquitin ligases and deubiquitinases involved, how ubiquitination and deubiquitination are regulated, and whether the underlying mechanisms are conserved from Drosophila to mammals. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

18 pages, 1625 KiB

Open AccessReview

Autophagy Regulation by Crosstalk between miRNAs and Ubiquitination System

by Junyan Qu and Zhenghong Lin

Int. J. Mol. Sci. 2021, 22(21), 11912; https://doi.org/10.3390/ijms222111912 - 3 Nov 2021

Cited by 11 | Viewed by 3115

Abstract

MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules encoded by endogenous genes with ~22 nucleotides which are involved in the regulation of post-transcriptional gene expression. Ubiquitination and deubiquitination are common post-translational modifications in eukaryotic cells and important pathways in regulating protein degradation and signal [...] Read more.

MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules encoded by endogenous genes with ~22 nucleotides which are involved in the regulation of post-transcriptional gene expression. Ubiquitination and deubiquitination are common post-translational modifications in eukaryotic cells and important pathways in regulating protein degradation and signal transduction, in which E3 ubiquitin ligases and deubiquitinases (DUBs) play a decisive role. MiRNA and ubiquitination are involved in the regulation of most biological processes, including autophagy. Furthermore, in recent years, the direct interaction between miRNA and E3 ubiquitin ligases or deubiquitinases has attracted much attention, and the cross-talk between miRNA and ubiquitination system has been proved to play key regulatory roles in a variety of diseases. In this review, we summarized the advances in autophagy regulation by crosstalk between miRNA and E3 ubiquitin ligases or deubiquitinases. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

22 pages, 2295 KiB

Open AccessReview

The Function of SUMOylation and Its Critical Roles in Cardiovascular Diseases and Potential Clinical Implications

by Congcong Du, Xu Chen, Qi Su, Wenbin Lu, Qiqi Wang, Hong Yuan, Zhenzhen Zhang, Xiaotong Wang, Hongmei Wu and Yitao Qi

Int. J. Mol. Sci. 2021, 22(19), 10618; https://doi.org/10.3390/ijms221910618 - 30 Sep 2021

Cited by 15 | Viewed by 3305

Abstract

Cardiovascular disease (CVD) is a common disease caused by many factors, including atherosclerosis, congenital heart disease, heart failure, and ischemic cardiomyopathy. CVD has been regarded as one of the most common diseases and has a severe impact on the life quality of patients. [...] Read more.

Cardiovascular disease (CVD) is a common disease caused by many factors, including atherosclerosis, congenital heart disease, heart failure, and ischemic cardiomyopathy. CVD has been regarded as one of the most common diseases and has a severe impact on the life quality of patients. The main features of CVD include high morbidity and mortality, which seriously threaten human health. SUMO proteins covalently conjugate lysine residues with a large number of substrate proteins, and SUMOylation regulates the function of target proteins and participates in cellular activities. Under certain pathological conditions, SUMOylation of proteins related to cardiovascular development and function are greatly changed. Numerous studies have suggested that SUMOylation of substrates plays critical roles in normal cardiovascular development and function. We reviewed the research progress of SUMOylation in cardiovascular development and function, and the regulation of protein SUMOylation may be applied as a potential therapeutic strategy for CVD treatment. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

14 pages, 654 KiB

Open AccessReview

The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer

by Jun-O Jin, Nidhi Puranik, Quyen Thu Bui, Dhananjay Yadav and Peter Chang-Whan Lee

Int. J. Mol. Sci. 2021, 22(17), 9629; https://doi.org/10.3390/ijms22179629 - 6 Sep 2021

Cited by 24 | Viewed by 4488

Abstract

The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation [...] Read more.

The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation can lead to a variety of clinical outcomes, including tumor formation and metastasis. Similarly, ubiquitination acts as a core component, which contributes to the alteration of cell signaling activity, dictating biosignal turnover and protein fates. As lung cancer acquires the most commonly mutated proteins, changes in the ubiquitination of the proteins contribute to the development of lung cancer. Various inhibitors targeting the ubiquitin system have been developed for clinical applications in lung cancer treatment. In this review, we summarize the current research advances in therapeutics for lung cancer by targeting the ubiquitin system. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

23 pages, 5873 KiB

Open AccessReview

Signaling Pathways Regulated by UBR Box-Containing E3 Ligases

by Jung Gi Kim, Ho-Chul Shin, Taewook Seo, Laxman Nawale, Goeun Han, Bo Yeon Kim, Seung Jun Kim and Hyunjoo Cha-Molstad

Int. J. Mol. Sci. 2021, 22(15), 8323; https://doi.org/10.3390/ijms22158323 - 3 Aug 2021

Cited by 26 | Viewed by 6175

Abstract

UBR box E3 ligases, also called N-recognins, are integral components of the N-degron pathway. Representative N-recognins include UBR1, UBR2, UBR4, and UBR5, and they bind destabilizing N-terminal residues, termed N-degrons. Understanding the molecular bases of their substrate recognition and the biological impact of [...] Read more.

UBR box E3 ligases, also called N-recognins, are integral components of the N-degron pathway. Representative N-recognins include UBR1, UBR2, UBR4, and UBR5, and they bind destabilizing N-terminal residues, termed N-degrons. Understanding the molecular bases of their substrate recognition and the biological impact of the clearance of their substrates on cellular signaling pathways can provide valuable insights into the regulation of these pathways. This review provides an overview of the current knowledge of the binding mechanism of UBR box N-recognin/N-degron interactions and their roles in signaling pathways linked to G-protein-coupled receptors, apoptosis, mitochondrial quality control, inflammation, and DNA damage. The targeting of these UBR box N-recognins can provide potential therapies to treat diseases such as cancer and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Ubiquitination and Deubiquitination in Cellular Homeostasis

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issues

Published Papers (25 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI