International Journal of Molecular Sciences

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15 pages, 4362 KiB

Open AccessArticle

Hydrophobic Tagging-Mediated Degradation of Transcription Coactivator SRC-1

by So Ra Choi, Hee Myeong Wang, Min Hyeon Shin and Hyun-Suk Lim

Int. J. Mol. Sci. 2021, 22(12), 6407; https://doi.org/10.3390/ijms22126407 - 15 Jun 2021

Cited by 19 | Viewed by 4051

Abstract

Steroid receptor coactivator-1 (SRC-1) is a transcription coactivator playing a pivotal role in mediating a wide range of signaling pathways by interacting with related transcription factors and nuclear receptors. Aberrantly elevated SRC-1 activity is associated with cancer metastasis and progression, and therefore, suppression [...] Read more.

Steroid receptor coactivator-1 (SRC-1) is a transcription coactivator playing a pivotal role in mediating a wide range of signaling pathways by interacting with related transcription factors and nuclear receptors. Aberrantly elevated SRC-1 activity is associated with cancer metastasis and progression, and therefore, suppression of SRC-1 is emerging as a promising therapeutic strategy. In this study, we developed a novel SRC-1 degrader for targeted degradation of cellular SRC-1. This molecule consists of a selective ligand for SRC-1 and a bulky hydrophobic group. Since the hydrophobic moiety on the protein surface could mimic a partially denatured hydrophobic region of a protein, SRC-1 could be recognized as an unfolded protein and experience the chaperone-mediated degradation in the cells through the ubiquitin–proteasome system (UPS). Our results demonstrate that a hydrophobic-tagged chimeric molecule is shown to significantly reduce cellular levels of SRC-1 and suppress cancer cell migration and invasion. Together, these results highlight that our SRC-1 degrader represents a novel class of therapeutic candidates for targeting cancer metastasis. Moreover, we believe that the hydrophobic tagging strategy would be widely applicable to develop peptide-based protein degraders with enhanced cellular activity. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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18 pages, 7472 KiB

Open AccessArticle

Long-Lasting Growth Hormone Regulated by the Ubiquitin-Proteasome System

by Myung-Sun Kim, Kyunggon Kim, Su Kyung Oh, Gidae Lee, Jin-Ock Kim, Lan Li, Jung-Hyun Park and Kwang-Hyun Baek

Int. J. Mol. Sci. 2021, 22(12), 6268; https://doi.org/10.3390/ijms22126268 - 10 Jun 2021

Viewed by 2970

Abstract

To increase the half-life of growth hormones, we proposed its long-lasting regulation through the ubiquitin-proteasome system (UPS). We identified lysine residues (K67, K141, and K166) that are involved in the ubiquitination of human growth hormone (hGH) using ubiquitination site prediction programs to validate [...] Read more.

To increase the half-life of growth hormones, we proposed its long-lasting regulation through the ubiquitin-proteasome system (UPS). We identified lysine residues (K67, K141, and K166) that are involved in the ubiquitination of human growth hormone (hGH) using ubiquitination site prediction programs to validate the ubiquitination sites, and then substituted these lysine residues with arginine residues. We identified the most effective substituent (K141R) to prevent ubiquitination and named it AUT-hGH. hGH was expressed and purified in the form of hGH-His, and ubiquitination was first verified at sites containing K141 in the blood stream. Through the study, we propose that AUT-hGH with an increased half-life could be used as a long-lasting hGH in the blood stream. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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25 pages, 8163 KiB

Open AccessArticle

CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation

by Tomas Lidak, Nikol Baloghova, Vladimir Korinek, Radislav Sedlacek, Jana Balounova, Petr Kasparek and Lukas Cermak

Int. J. Mol. Sci. 2021, 22(10), 5394; https://doi.org/10.3390/ijms22105394 - 20 May 2021

Cited by 14 | Viewed by 4909

Abstract

Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an “ancient” RNA-induced silencing complex (RISC) [...] Read more.

Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an “ancient” RNA-induced silencing complex (RISC) complex RNA helicase. We show that DCAF12 controls the MOV10 protein level via its C-terminal motif in a proteasome- and CRL-dependent manner. Next, we generated Dcaf12 knockout mice and demonstrated that the DCAF12-mediated degradation of MOV10 is conserved in mice and humans. Detailed analysis of Dcaf12-deficient mice revealed that their testes produce fewer mature sperms, phenotype accompanied by elevated MOV10 and imbalance in meiotic markers SCP3 and γ-H2AX. Additionally, the percentages of splenic CD4⁺ T and natural killer T (NKT) cell populations were significantly altered. In vitro, activated Dcaf12-deficient T cells displayed inappropriately stabilized MOV10 and increased levels of activated caspases. In summary, we identified MOV10 as a novel substrate of CRL4-DCAF12 and demonstrated the biological relevance of the DCAF12-MOV10 pathway in spermatogenesis and T cell activation. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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18 pages, 3096 KiB

Open AccessArticle

A Proteomic Approach for Systematic Mapping of Substrates of Human Deubiquitinating Enzymes

by Juanma Ramirez, Gorka Prieto, Anne Olazabal-Herrero, Eva Borràs, Elvira Fernandez-Vigo, Unai Alduntzin, Nerea Osinalde, Javier Beaskoetxea, Benoit Lectez, Kerman Aloria, Jose Antonio Rodriguez, Alberto Paradela, Eduard Sabidó, Javier Muñoz, Fernando Corrales, Jesus M. Arizmendi and Ugo Mayor

Int. J. Mol. Sci. 2021, 22(9), 4851; https://doi.org/10.3390/ijms22094851 - 3 May 2021

Cited by 7 | Viewed by 4903

Abstract

The human genome contains nearly 100 deubiquitinating enzymes (DUBs) responsible for removing ubiquitin moieties from a large variety of substrates. Which DUBs are responsible for targeting which substrates remain mostly unknown. Here we implement the ^bioUb approach to identify DUB substrates in [...] Read more.

The human genome contains nearly 100 deubiquitinating enzymes (DUBs) responsible for removing ubiquitin moieties from a large variety of substrates. Which DUBs are responsible for targeting which substrates remain mostly unknown. Here we implement the ^bioUb approach to identify DUB substrates in a systematic manner, combining gene silencing and proteomics analyses. Silencing of individual DUB enzymes is used to reduce their ubiquitin deconjugating activity, leading to an increase of the ubiquitination of their substrates, which can then be isolated and identified. We report here quantitative proteomic data of the putative substrates of 5 human DUBs. Furthermore, we have built a novel interactive database of DUB substrates to provide easy access to our data and collect DUB proteome data from other groups as a reference resource in the DUB substrates research field. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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10 pages, 5583 KiB

Open AccessArticle

Erk1/2 Inactivation-Induced c-Jun Degradation Is Regulated by Protein Phosphatases, UBE2d3, and the C-Terminus of c-Jun

by Weiming Ouyang and David M. Frucht

Int. J. Mol. Sci. 2021, 22(8), 3889; https://doi.org/10.3390/ijms22083889 - 9 Apr 2021

Cited by 5 | Viewed by 2696

Abstract

Constitutive photomorphogenic 1 (COP1) is the ubiquitin E3 ligase that mediates degradation of c-Jun protein upon Erk1/2 inactivation. It remains unknown how this protein degradation pathway is regulated. In this study, we investigated the roles of protein phosphatases, ubiquitin-conjugating E2 enzymes (UBE2), and [...] Read more.

Constitutive photomorphogenic 1 (COP1) is the ubiquitin E3 ligase that mediates degradation of c-Jun protein upon Erk1/2 inactivation. It remains unknown how this protein degradation pathway is regulated. In this study, we investigated the roles of protein phosphatases, ubiquitin-conjugating E2 enzymes (UBE2), and an intrinsic motif of c-Jun in regulating this degradation pathway. By using pharmacological inhibitors and/or gene knockdown techniques, we identified protein phosphatase 1 (PP1) and PP2A as the phosphatases and UBE23d as the UBE2 promoting c-Jun degradation, triggered by Erk1/2 inactivation. In addition, we report that the C-terminus of c-Jun protein facilitates its degradation. The addition of a C-terminal tag or deletion of the last four amino acid residues from the C-terminus of c-Jun protects it from degradation under Erk1/2-inactivating conditions. Taken together, this study reveals that the Erk1/2 inactivation-triggered and COP1-mediated c-Jun degradation is extrinsically and intrinsically regulated, providing a new understanding of the mechanisms underlying this protein degradation pathway. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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26 pages, 2580 KiB

Open AccessArticle

Diverse Evolution in 111 Plant Genomes Reveals Purifying and Dosage Balancing Selection Models for F-Box Genes

by Zhihua Hua

Int. J. Mol. Sci. 2021, 22(2), 871; https://doi.org/10.3390/ijms22020871 - 16 Jan 2021

Cited by 9 | Viewed by 3376

Abstract

The F-box proteins function as substrate receptors to determine the specificity of Skp1-Cul1-F-box ubiquitin ligases. Genomic studies revealed large and diverse sizes of the F-box gene superfamily across plant species. Our previous studies suggested that the plant F-box gene superfamily is under genomic [...] Read more.

The F-box proteins function as substrate receptors to determine the specificity of Skp1-Cul1-F-box ubiquitin ligases. Genomic studies revealed large and diverse sizes of the F-box gene superfamily across plant species. Our previous studies suggested that the plant F-box gene superfamily is under genomic drift evolution promoted by epigenomic programming. However, how the size of the superfamily drifts across plant genomes is currently unknown. Through a large-scale genomic and phylogenetic comparison of the F-box gene superfamily covering 110 green plants and one red algal species, I discovered four distinct groups of plant F-box genes with diverse evolutionary processes. While the members in Clusters 1 and 2 are species/lineage-specific, those in Clusters 3 and 4 are present in over 46 plant genomes. Statistical modeling suggests that F-box genes from the former two groups are skewed toward fewer species and more paralogs compared to those of the latter two groups whose presence frequency and sizes in plant genomes follow a random statistical model. The enrichment of known Arabidopsis F-box genes in Clusters 3 and 4, along with comprehensive biochemical evidence showing that Arabidopsis members in Cluster 4 interact with the Arabidopsis Skp1-like 1 (ASK1), demonstrates over-representation of active F-box genes in these two groups. Collectively, I propose purifying and dosage balancing selection models to explain the lineage/species-specific duplications and expansions of F-box genes in plant genomes. The purifying selection model suggests that most, if not all, lineage/species-specific F-box genes are detrimental and are thus kept at low frequencies in plant genomes. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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Review

Jump to: Research

19 pages, 13434 KiB

Open AccessReview

Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases

by Seonghyeon Moon, Srinivasan Muniyappan, Sung-Bae Lee and Byung-Hoon Lee

Int. J. Mol. Sci. 2021, 22(12), 6213; https://doi.org/10.3390/ijms22126213 - 9 Jun 2021

Cited by 14 | Viewed by 5922

Abstract

The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of [...] Read more.

The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases–USP14, RPN11, and UCH37–are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome’s conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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20 pages, 1539 KiB

Open AccessReview

Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

by So-Hee Kim and Kwang-Hyun Baek

Int. J. Mol. Sci. 2021, 22(12), 6173; https://doi.org/10.3390/ijms22126173 - 8 Jun 2021

Cited by 28 | Viewed by 17303

Abstract

Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors [...] Read more.

Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors of the glycolysis pathway in cancer cells, and these signaling factors are ubiquitinated/deubiquitinated via the ubiquitin–proteasome system (UPS). Depending on the target protein, DUBs act as both an oncoprotein and a tumor suppressor. Since the degradation of tumor suppressors and stabilization of oncoproteins by either negative regulation by E3 ligases or positive regulation of DUBs, respectively, promote tumorigenesis, it is necessary to suppress these DUBs by applying appropriate inhibitors or small molecules. Therefore, we propose that the DUBs and their inhibitors related to the Warburg effect are potential anticancer targets. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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13 pages, 235 KiB

Open AccessReview

Ubiquitination and Deubiquitination in Oral Disease

by Sachio Tsuchida and Tomohiro Nakayama

Int. J. Mol. Sci. 2021, 22(11), 5488; https://doi.org/10.3390/ijms22115488 - 23 May 2021

Cited by 6 | Viewed by 3477

Abstract

Oral health is an integral part of the general health and well-being of individuals. The presence of oral disease is potentially indicative of a number of systemic diseases and may contribute to their early diagnosis and treatment. The ubiquitin (Ub) system has been [...] Read more.

Oral health is an integral part of the general health and well-being of individuals. The presence of oral disease is potentially indicative of a number of systemic diseases and may contribute to their early diagnosis and treatment. The ubiquitin (Ub) system has been shown to play a role in cellular immune response, cellular development, and programmed cell death. Ubiquitination is a post-translational modification that occurs in eukaryotes. Its mechanism involves a number of factors, including Ub-activating enzymes, Ub-conjugating enzymes, and Ub protein ligases. Deubiquitinating enzymes, which are proteases that reversely modify proteins by removing Ub or Ub-like molecules or remodeling Ub chains on target proteins, have recently been regarded as crucial regulators of ubiquitination-mediated degradation and are known to significantly affect cellular pathways, a number of biological processes, DNA damage response, and DNA repair pathways. Research has increasingly shown evidence of the relationship between ubiquitination, deubiquitination, and oral disease. This review investigates recent progress in discoveries in diseased oral sites and discusses the roles of ubiquitination and deubiquitination in oral disease. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

17 pages, 5596 KiB

Open AccessReview

Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development

by Charles Ducker and Peter E. Shaw

Int. J. Mol. Sci. 2021, 22(10), 5119; https://doi.org/10.3390/ijms22105119 - 12 May 2021

Cited by 9 | Viewed by 4487

Abstract

Genome expansion, whole genome and gene duplication events during metazoan evolution produced an extensive family of ETS genes whose members express transcription factors with a conserved winged helix-turn-helix DNA-binding domain. Unravelling their biological roles has proved challenging with functional redundancy manifest in overlapping [...] Read more.

Genome expansion, whole genome and gene duplication events during metazoan evolution produced an extensive family of ETS genes whose members express transcription factors with a conserved winged helix-turn-helix DNA-binding domain. Unravelling their biological roles has proved challenging with functional redundancy manifest in overlapping expression patterns, a common consensus DNA-binding motif and responsiveness to mitogen-activated protein kinase signalling. Key determinants of the cellular repertoire of ETS proteins are their stability and turnover, controlled largely by the actions of selective E3 ubiquitin ligases and deubiquitinases. Here we discuss the known relationships between ETS proteins and enzymes that determine their ubiquitin status, their integration with other developmental signal transduction pathways and how suppression of ETS protein ubiquitination contributes to the malignant cell phenotype in multiple cancers. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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18 pages, 1628 KiB

Open AccessReview

The Multifaceted Roles of USP15 in Signal Transduction

by Tanuza Das, Eun Joo Song and Eunice EunKyeong Kim

Int. J. Mol. Sci. 2021, 22(9), 4728; https://doi.org/10.3390/ijms22094728 - 29 Apr 2021

Cited by 25 | Viewed by 5913

Abstract

Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly [...] Read more.

Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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17 pages, 1435 KiB

Open AccessReview

Role of Virally-Encoded Deubiquitinating Enzymes in Regulation of the Virus Life Cycle

by Jessica Proulx, Kathleen Borgmann and In-Woo Park

Int. J. Mol. Sci. 2021, 22(9), 4438; https://doi.org/10.3390/ijms22094438 - 23 Apr 2021

Cited by 17 | Viewed by 3894

Abstract

The ubiquitin (Ub) proteasome system (UPS) plays a pivotal role in regulation of numerous cellular processes, including innate and adaptive immune responses that are essential for restriction of the virus life cycle in the infected cells. Deubiquitination by the deubiquitinating enzyme, deubiquitinase (DUB), [...] Read more.

The ubiquitin (Ub) proteasome system (UPS) plays a pivotal role in regulation of numerous cellular processes, including innate and adaptive immune responses that are essential for restriction of the virus life cycle in the infected cells. Deubiquitination by the deubiquitinating enzyme, deubiquitinase (DUB), is a reversible molecular process to remove Ub or Ub chains from the target proteins. Deubiquitination is an integral strategy within the UPS in regulating survival and proliferation of the infecting virus and the virus-invaded cells. Many viruses in the infected cells are reported to encode viral DUB, and these vial DUBs actively disrupt cellular Ub-dependent processes to suppress host antiviral immune response, enhancing virus replication and thus proliferation. This review surveys the types of DUBs encoded by different viruses and their molecular processes for how the infecting viruses take advantage of the DUB system to evade the host immune response and expedite their replication. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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37 pages, 2003 KiB

Open AccessReview

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

by Choong-Sil Lee, Seungyeon Kim, Gyuho Hwang and Jaewhan Song

Int. J. Mol. Sci. 2021, 22(9), 4352; https://doi.org/10.3390/ijms22094352 - 21 Apr 2021

Cited by 13 | Viewed by 4332

Abstract

The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways [...] Read more.

The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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26 pages, 8815 KiB

Open AccessReview

Post-Translational Modifications of Retroviral HIV-1 Gag Precursors: An Overview of Their Biological Role

by Charlotte Bussienne, Roland Marquet, Jean-Christophe Paillart and Serena Bernacchi

Int. J. Mol. Sci. 2021, 22(6), 2871; https://doi.org/10.3390/ijms22062871 - 11 Mar 2021

Cited by 13 | Viewed by 4553

Abstract

Protein post-translational modifications (PTMs) play key roles in eukaryotes since they finely regulate numerous mechanisms used to diversify the protein functions and to modulate their signaling networks. Besides, these chemical modifications also take part in the viral hijacking of the host, and also [...] Read more.

Protein post-translational modifications (PTMs) play key roles in eukaryotes since they finely regulate numerous mechanisms used to diversify the protein functions and to modulate their signaling networks. Besides, these chemical modifications also take part in the viral hijacking of the host, and also contribute to the cellular response to viral infections. All domains of the human immunodeficiency virus type 1 (HIV-1) Gag precursor of 55-kDa (Pr55^Gag), which is the central actor for viral RNA specific recruitment and genome packaging, are post-translationally modified. In this review, we summarize the current knowledge about HIV-1 Pr55^Gag PTMs such as myristoylation, phosphorylation, ubiquitination, sumoylation, methylation, and ISGylation in order to figure out how these modifications affect the precursor functions and viral replication. Indeed, in HIV-1, PTMs regulate the precursor trafficking between cell compartments and its anchoring at the plasma membrane, where viral assembly occurs. Interestingly, PTMs also allow Pr55^Gag to hijack the cell machinery to achieve viral budding as they drive recognition between viral proteins or cellular components such as the ESCRT machinery. Finally, we will describe and compare PTMs of several other retroviral Gag proteins to give a global overview of their role in the retroviral life cycle. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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30 pages, 1588 KiB

Open AccessReview

How Is the Fidelity of Proteins Ensured in Terms of Both Quality and Quantity at the Endoplasmic Reticulum? Mechanistic Insights into E3 Ubiquitin Ligases

by Ji An Kang and Young Joo Jeon

Int. J. Mol. Sci. 2021, 22(4), 2078; https://doi.org/10.3390/ijms22042078 - 19 Feb 2021

Cited by 7 | Viewed by 5524

Abstract

The endoplasmic reticulum (ER) is an interconnected organelle that plays fundamental roles in the biosynthesis, folding, stabilization, maturation, and trafficking of secretory and transmembrane proteins. It is the largest organelle and critically modulates nearly all aspects of life. Therefore, in the endoplasmic reticulum, [...] Read more.

The endoplasmic reticulum (ER) is an interconnected organelle that plays fundamental roles in the biosynthesis, folding, stabilization, maturation, and trafficking of secretory and transmembrane proteins. It is the largest organelle and critically modulates nearly all aspects of life. Therefore, in the endoplasmic reticulum, an enormous investment of resources, including chaperones and protein folding facilitators, is dedicated to adequate protein maturation and delivery to final destinations. Unfortunately, the folding and assembly of proteins can be quite error-prone, which leads to the generation of misfolded proteins. Notably, protein homeostasis, referred to as proteostasis, is constantly exposed to danger by flows of misfolded proteins and subsequent protein aggregates. To maintain proteostasis, the ER triages and eliminates terminally misfolded proteins by delivering substrates to the ubiquitin–proteasome system (UPS) or to the lysosome, which is termed ER-associated degradation (ERAD) or ER-phagy, respectively. ERAD not only eliminates misfolded or unassembled proteins via protein quality control but also fine-tunes correctly folded proteins via protein quantity control. Intriguingly, the diversity and distinctive nature of E3 ubiquitin ligases determine efficiency, complexity, and specificity of ubiquitination during ERAD. ER-phagy utilizes the core autophagy machinery and eliminates ERAD-resistant misfolded proteins. Here, we conceptually outline not only ubiquitination machinery but also catalytic mechanisms of E3 ubiquitin ligases. Further, we discuss the mechanistic insights into E3 ubiquitin ligases involved in the two guardian pathways in the ER, ERAD and ER-phagy. Finally, we provide the molecular mechanisms by which ERAD and ER-phagy conduct not only protein quality control but also protein quantity control to ensure proteostasis and subsequent organismal homeostasis. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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21 pages, 1108 KiB

Open AccessReview

The Roles of the Ubiquitin–Proteasome System in the Endoplasmic Reticulum Stress Pathway

by Junyan Qu, Tingting Zou and Zhenghong Lin

Int. J. Mol. Sci. 2021, 22(4), 1526; https://doi.org/10.3390/ijms22041526 - 3 Feb 2021

Cited by 59 | Viewed by 7481

Abstract

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells, which is essential for synthesis, processing, sorting of protein and lipid metabolism. However, the cells activate a defense mechanism called endoplasmic reticulum stress (ER stress) response and initiate unfolded protein response [...] Read more.

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells, which is essential for synthesis, processing, sorting of protein and lipid metabolism. However, the cells activate a defense mechanism called endoplasmic reticulum stress (ER stress) response and initiate unfolded protein response (UPR) as the unfolded proteins exceed the folding capacity of the ER due to the environmental influences or increased protein synthesis. ER stress can mediate many cellular processes, including autophagy, apoptosis and senescence. The ubiquitin-proteasome system (UPS) is involved in the degradation of more than 80% of proteins in the cells. Today, increasing numbers of studies have shown that the two important components of UPS, E3 ubiquitin ligases and deubiquitinases (DUBs), are tightly related to ER stress. In this review, we summarized the regulation of the E3 ubiquitin ligases and DUBs in ER stress. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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32 pages, 11381 KiB

Open AccessReview

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

by Hiroshi Kitamura and Mayuko Hashimoto

Int. J. Mol. Sci. 2021, 22(3), 1209; https://doi.org/10.3390/ijms22031209 - 26 Jan 2021

Cited by 38 | Viewed by 7293

Abstract

Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally [...] Read more.

Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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13 pages, 1716 KiB

Open AccessReview

Structural Insights into Ankyrin Repeat-Containing Proteins and Their Influence in Ubiquitylation

by Emma I. Kane and Donald E. Spratt

Int. J. Mol. Sci. 2021, 22(2), 609; https://doi.org/10.3390/ijms22020609 - 9 Jan 2021

Cited by 18 | Viewed by 4502

Abstract

Ankyrin repeat (AR) domains are considered the most abundant repeat motif found in eukaryotic proteins. AR domains are predominantly known to mediate specific protein–protein interactions (PPIs) without necessarily recognizing specific primary sequences, nor requiring strict conformity within its own primary sequence. This promiscuity [...] Read more.

Ankyrin repeat (AR) domains are considered the most abundant repeat motif found in eukaryotic proteins. AR domains are predominantly known to mediate specific protein–protein interactions (PPIs) without necessarily recognizing specific primary sequences, nor requiring strict conformity within its own primary sequence. This promiscuity allows for one AR domain to recognize and bind to a variety of intracellular substrates, suggesting that AR-containing proteins may be involved in a wide array of functions. Many AR-containing proteins serve a critical role in biological processes including the ubiquitylation signaling pathway (USP). There is also strong evidence that AR-containing protein malfunction are associated with several neurological diseases and disorders. In this review, the structure and mechanism of key AR-containing proteins are discussed to suggest and/or identify how each protein utilizes their AR domains to support ubiquitylation and the cascading pathways that follow upon substrate modification. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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Open AccessReview

Emerging Roles of USP18: From Biology to Pathophysiology

by Ji An Kang and Young Joo Jeon

Int. J. Mol. Sci. 2020, 21(18), 6825; https://doi.org/10.3390/ijms21186825 - 17 Sep 2020

Cited by 38 | Viewed by 6274

Abstract

Eukaryotic proteomes are enormously sophisticated through versatile post-translational modifications (PTMs) of proteins. A large variety of code generated via PTMs of proteins by ubiquitin (ubiquitination) and ubiquitin-like proteins (Ubls), such as interferon (IFN)-stimulated gene 15 (ISG15), small ubiquitin-related modifier (SUMO) and neural precursor [...] Read more.

Eukaryotic proteomes are enormously sophisticated through versatile post-translational modifications (PTMs) of proteins. A large variety of code generated via PTMs of proteins by ubiquitin (ubiquitination) and ubiquitin-like proteins (Ubls), such as interferon (IFN)-stimulated gene 15 (ISG15), small ubiquitin-related modifier (SUMO) and neural precursor cell expressed, developmentally downregulated 8 (NEDD8), not only provides distinct signals but also orchestrates a plethora of biological processes, thereby underscoring the necessity for sophisticated and fine-tuned mechanisms of code regulation. Deubiquitinases (DUBs) play a pivotal role in the disassembly of the complex code and removal of the signal. Ubiquitin-specific protease 18 (USP18), originally referred to as UBP43, is a major DUB that reverses the PTM of target proteins by ISG15 (ISGylation). Intriguingly, USP18 is a multifaceted protein that not only removes ISG15 or ubiquitin from conjugated proteins in a deconjugating activity-dependent manner but also acts as a negative modulator of type I IFN signaling, irrespective of its catalytic activity. The function of USP18 has become gradually clear, but not yet been completely addressed. In this review, we summarize recent advances in our understanding of the multifaceted roles of USP18. We also highlight new insights into how USP18 is implicated not only in physiology but also in pathogenesis of various human diseases, involving infectious diseases, neurological disorders, and cancers. Eventually, we integrate a discussion of the potential of therapeutic interventions for targeting USP18 for disease treatment. Full article

(This article belongs to the Special Issue Ubiquitin-Conjugating or Deubiquitinating Enzymes in Signal Transduction Pathways)

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