Functional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics

Mapping Intimacies ◽

10.5772/intechopen.100534 ◽

2021 ◽

Author(s):

Julius Tieroyaare Dongdem ◽

Cletus Adiyaga Wezena

Keyword(s):

Therapeutic Potential ◽

Protein Complexes ◽

Ring Finger ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Phd Finger ◽

E3 Ligases ◽

Cellular Processes ◽

Future Drug ◽

Ubiquitin Conjugating Enzyme

E3 ubiquitin ligases of which there are >600 putative in humans, constitute a family of highly heterogeneous proteins and protein complexes that are the ultimate enzymes responsible for the recruitment of an ubiquitin loaded E2 ubiquitin-conjugating enzyme, recognise the appropriate protein substrate and directly or indirectly transfer the ubiquitin load onto the substrate. The aftermath of an E3 ligase activity is usually the formation of an isopeptide bond between the free carboxylate group of ubiquitin’s C-terminal Gly76 and an ε-amino group of the substrate’s Lys, even though non-canonical ubiquitylation on non-amine groups of target proteins have been observed. E3 ligases are grouped into four distinct families: HECT, RING-finger/U-box, RBR and PHD-finger. E3 ubiquitin ligases play critical roles in subcellular signalling cascades in eukaryotes. Dysfunctional E3 ubiquitin ligases therefore tend to inflict dramatic effects on human health and may result in the development of various diseases including Parkinson’s, Amyotrophic Lateral Sclerosis, Alzheimer’s, cancer, etc. Being regulators of numerous cellular processes, some E3 ubiquitin ligases have become potential targets for therapy. This chapter will present a comprehensive review of up-to-date findings in E3 ligases, their role in the pathology of disease and therapeutic potential for future drug development.

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Comprehensive Analysis of E3 Ubiquitin Ligases Reveals Ring Finger Protein 223 as a Novel Oncogene Activated by KLF4 in Pancreatic Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.738709 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lei Feng ◽

Jieqing Wang ◽

Jianmin Zhang ◽

Jingfang Diao ◽

Longguang He ◽

...

Keyword(s):

Pancreatic Cancer ◽

Transcriptional Activation ◽

Prognostic Significance ◽

Ring Finger ◽

Ubiquitin Ligases ◽

The Cancer Genome Atlas ◽

Differentially Expressed ◽

E3 Ubiquitin Ligases ◽

E3 Ligases ◽

Elevated Expression

Pancreatic cancer is one of the major malignancies and causes of mortality worldwide. E3 ubiquitin–protein ligases transfer activated ubiquitin from ubiquitin-conjugating enzymes to protein substrates and confer substrate specificity in cancer. In this study, we first downloaded data from The Cancer Genome Atlas pancreatic adenocarcinoma dataset, acquired all 27 differentially expressed genes (DEGs), and identified genomic alterations. Then, the prognostic significance of DEGs was analyzed, and eight DEGs (MECOM, CBLC, MARCHF4, RNF166, TRIM46, LONRF3, RNF39, and RNF223) and two clinical parameters (pathological N stage and T stage) exhibited prognostic significance. RNF223 showed independent significance as an unfavorable prognostic marker and was chosen for subsequent analysis. Next, the function of RNF223 in the pancreatic cancer cell lines ASPC-1 and PANC-1 was investigated, and RNF223 silencing promoted pancreatic cancer growth and migration. To explore the potential targets and pathways of RNF223 in pancreatic cancer, quantitative proteomics was applied to analyze differentially expressed proteins, and metabolism-related pathways were primarily enriched. Finally, the reason for the elevated expression of RNF223 was analyzed, and KLF4 was shown to contribute to the increased expression of RNF233. In conclusion, this study comprehensively analyzed the clinical significance of E3 ligases. Functional assays revealed that RNF223 promotes cancer by regulating cell metabolism. Finally, the elevated expression of RNF223 was attributed to KLF4-mediated transcriptional activation. This study broadens our knowledge regarding E3 ubiquitin ligases and signal transduction and provides novel markers and therapeutic targets in pancreatic cancer.

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E3 ubiquitin ligase components in GtoPdb v.2021.3

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f1023/2021.3 ◽

2021 ◽

Vol 2021 (3) ◽

Author(s):

Elena Faccenda ◽

Robert Layfield

Keyword(s):

Cell Cycle Progression ◽

Protein Complexes ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Post Translational Modification ◽

Protein Substrates ◽

Cellular Processes ◽

Ubiquitin Molecule ◽

E2 Enzymes ◽

Ubiquitin Conjugating Enzymes

Ubiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [19]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction. E3 ubiquitin ligases, of which there are >600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex.

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The p97 cofactor Ubxn7 facilitates replisome disassembly during S-phase

10.1101/2021.12.16.472925 ◽

2021 ◽

Author(s):

Zeynep Tarcan ◽

Divyasree Poovathumkadavil ◽

Aggeliki Skagia ◽

Agnieszka Gambus

Keyword(s):

Dna Replication ◽

Molecular Mechanism ◽

Protein Complexes ◽

Ubiquitin Ligases ◽

S Phase ◽

E3 Ubiquitin Ligases ◽

Replication Machinery ◽

Replicative Helicase ◽

Cellular Processes ◽

Eukaryotic Dna

Complex cellular processes are driven by the regulated assembly and disassembly of large multi-protein complexes. In eukaryotic DNA replication, whilst we are beginning to understand the molecular mechanism for assembly of the replication machinery (replisome), we still know relatively little about the regulation of its disassembly at replication termination. Over recent years, the first elements of this process have emerged, revealing that the replicative helicase, at the heart of the replisome, is polyubiquitylated prior to unloading and that this unloading requires p97 segregase activity. Two different E3 ubiquitin ligases are now known to ubiquitylate the helicase under different conditions: Cul2Lrr1 and TRAIP. Here we have found two p97 cofactors, Ubxn7 and Faf1, which can interact with p97 during replisome disassembly in S-phase. Only Ubxn7 however facilitates efficient replisome disassembly through its interaction with both Cul2Lrr1 and p97. Our data therefore characterise Ubxn7 as the first substrate-specific p97 cofactor regulating replisome disassembly in vertebrates.

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E3 ubiquitin ligases: styles, structures and functions

Molecular Biomedicine ◽

10.1186/s43556-021-00043-2 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Quan Yang ◽

Jinyao Zhao ◽

Dan Chen ◽

Yang Wang

Keyword(s):

Cancer Progression ◽

Large Family ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Therapeutic Approaches ◽

E3 Ligases ◽

Promising Target ◽

Stress Signal ◽

Ubiquitin Conjugating Enzyme ◽

Almost All

AbstractE3 ubiquitin ligases are a large family of enzymes that join in a three-enzyme ubiquitination cascade together with ubiquitin activating enzyme E1 and ubiquitin conjugating enzyme E2. E3 ubiquitin ligases play an essential role in catalyzing the ubiquitination process and transferring ubiquitin protein to attach the lysine site of targeted substrates. Importantly, ubiquitination modification is involved in almost all life activities of eukaryotes. Thus, E3 ligases might be involved in regulating various biological processes and cellular responses to stress signal associated with cancer development. Thanks to their multi-functions, E3 ligases can be a promising target of cancer therapy. A deeper understanding of the regulatory mechanisms of E3 ligases in tumorigenesis will help to find new prognostic markers and accelerate the growth of anticancer therapeutic approaches. In general, we mainly introduce the classifications of E3 ligases and their important roles in cancer progression and therapeutic functions.

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RBR E3 ubiquitin ligases: new structures, new insights, new questions

Biochemical Journal ◽

10.1042/bj20140006 ◽

2014 ◽

Vol 458 (3) ◽

pp. 421-437 ◽

Cited By ~ 131

Author(s):

Donald E. Spratt ◽

Helen Walden ◽

Gary S. Shaw

Keyword(s):

Catalytic Domain ◽

Three Dimensional ◽

Ring Finger ◽

Ubiquitin Ligases ◽

Cysteine Residue ◽

Protein Domain ◽

E3 Ubiquitin Ligases ◽

Ubiquitin Chain ◽

E3 Ligases ◽

Catalytic Cysteine

The RBR (RING-BetweenRING-RING) or TRIAD [two RING fingers and a DRIL (double RING finger linked)] E3 ubiquitin ligases comprise a group of 12 complex multidomain enzymes. This unique family of E3 ligases includes parkin, whose dysfunction is linked to the pathogenesis of early-onset Parkinson's disease, and HOIP (HOIL-1-interacting protein) and HOIL-1 (haem-oxidized IRP2 ubiquitin ligase 1), members of the LUBAC (linear ubiquitin chain assembly complex). The RBR E3 ligases share common features with both the larger RING and HECT (homologous with E6-associated protein C-terminus) E3 ligase families, directly catalysing ubiquitin transfer from an intrinsic catalytic cysteine housed in the C-terminal domain, as well as recruiting thioester-bound E2 enzymes via a RING domain. Recent three-dimensional structures and biochemical findings of the RBRs have revealed novel protein domain folds not previously envisioned and some surprising modes of regulation that have raised many questions. This has required renaming two of the domains in the RBR E3 ligases to more accurately reflect their structures and functions: the C-terminal Rcat (required-for-catalysis) domain, essential for catalytic activity, and a central BRcat (benign-catalytic) domain that adopts the same fold as the Rcat, but lacks a catalytic cysteine residue and ubiquitination activity. The present review discusses how three-dimensional structures of RBR (RING1-BRcat-Rcat) E3 ligases have provided new insights into our understanding of the biochemical mechanisms of these important enzymes in ubiquitin biology.

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E3 ubiquitin ligase components (version 2019.5) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f1023/2019.5 ◽

2019 ◽

Vol 2019 (5) ◽

Author(s):

Elena Faccenda ◽

Robert Layfield

Keyword(s):

Cell Cycle Progression ◽

Protein Complexes ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Post Translational Modification ◽

Protein Substrates ◽

Cellular Processes ◽

Ubiquitin Molecule ◽

E2 Enzymes ◽

Ubiquitin Conjugating Enzymes

Ubiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [16]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction. E3 ubiquitin ligases, of which there are >600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex.

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Comprehensive database of human E3 ubiquitin ligases: application to aquaporin-2 regulation

Physiological Genomics ◽

10.1152/physiolgenomics.00031.2016 ◽

2016 ◽

Vol 48 (7) ◽

pp. 502-512 ◽

Cited By ~ 31

Author(s):

Barbara Medvar ◽

Viswanathan Raghuram ◽

Trairak Pisitkun ◽

Abhijit Sarkar ◽

Mark A. Knepper

Keyword(s):

Human Genome ◽

Large Scale ◽

E3 Ligase ◽

Ubiquitin Ligases ◽

Bayes Rule ◽

E3 Ubiquitin Ligases ◽

E3 Ligases ◽

Aquaporin 2 ◽

Large Scale Data ◽

Level Data

Aquaporin-2 (AQP2) is regulated in part via vasopressin-mediated changes in protein half-life that are in turn dependent on AQP2 ubiquitination. Here we addressed the question, “What E3 ubiquitin ligase is most likely to be responsible for AQP2 ubiquitination?” using large-scale data integration based on Bayes' rule. The first step was to bioinformatically identify all E3 ligase genes coded by the human genome. The 377 E3 ubiquitin ligases identified in the human genome, consisting predominant of HECT, RING, and U-box proteins, have been used to create a publically accessible and downloadable online database ( https://hpcwebapps.cit.nih.gov/ESBL/Database/E3-ligases/ ). We also curated a second database of E3 ligase accessory proteins that included BTB domain proteins, cullins, SOCS-box proteins, and F-box proteins. Using Bayes' theorem to integrate information from multiple large-scale proteomic and transcriptomic datasets, we ranked these 377 E3 ligases with respect to their probability of interaction with AQP2. Application of Bayes' rule identified the E3 ligases most likely to interact with AQP2 as (in order of probability): NEDD4 and NEDD4L (tied for first), AMFR, STUB1, ITCH, ZFPL1. Significantly, the two E3 ligases tied for top rank have also been studied extensively in the reductionist literature as regulatory proteins in renal tubule epithelia. The concordance of conclusions from reductionist and systems-level data provides strong motivation for further studies of the roles of NEDD4 and NEDD4L in the regulation of AQP2 protein turnover.

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