High incidence of ubiquitin-like domains in human ubiquitin-specific proteases.
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ABSTRACT:
SUBMITTER: Zhu X
PROVIDER: S-EPMC7167984 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.
| S-EPMC8469789 | biostudies-literature
Project description:affy_ath_2012_05 - affy_ath_2012_05 - The main objective is to determinate the influence of Ubiquitin-Like Proteases in plant transcriptional modulation. The experiment will also allow us to find what transcriptional cues are particularly affected in the mutants relatively to wild-type.-Seeds were stratified for 3 days at 4ºC in the dark. Afterwards, seeds were surface sterilized, sown onto MS media and grown at 23ºC, with 100 µE light condition, in long days (16h L/8h D). Each MS plate was dived in four, corresponding to a genotype (Col, AB, SIZ1 or SAB), and 10 seeds were sown per genotype. After 10 days, seedlings were collected and frozen in liquid nitrogen. Each replicate was made of ~40 seedlings coming from 4 different MS plates. Frozen plant material was grounded in an eppendorf tube using a mini pestle. RNA was extracted using RNeasy Plant Mini kit (QIAGEN cat.74904), following the manufacturer instructions (QIAGEN, Hilden, Germany). The RNA samples were DNase treated (Recombinant DNase I, Takara Biotechnology, Dalian, China) and subsequently cleaned by column using RNeasy Plant Mini kit (QIAGEN, Hilden, Germany). 12 arrays - ATH1; gene knock out Col [wild type] AB [knock out / insertional mutagen /T-Dna] SIZ1 [knock out / insertional mutagen /T-Dna] SAB [knock out / insertional mutagen /T-Dna] . More information about this study can be found at : http://urgv.evry.inra.fr/cgi-bin/projects/CATdb/consult_project.pl?project_id=326
2013-09-01 | E-GEOD-43883 | biostudies-arrayexpress
Project description:affy_ath_2012_05 - affy_ath_2012_05 - The main objective is to determinate the influence of Ubiquitin-Like Proteases in plant transcriptional modulation. The experiment will also allow us to find what transcriptional cues are particularly affected in the mutants relatively to wild-type.-Seeds were stratified for 3 days at 4ºC in the dark. Afterwards, seeds were surface sterilized, sown onto MS media and grown at 23ºC, with 100 µE light condition, in long days (16h L/8h D). Each MS plate was dived in four, corresponding to a genotype (Col, AB, SIZ1 or SAB), and 10 seeds were sown per genotype. After 10 days, seedlings were collected and frozen in liquid nitrogen. Each replicate was made of ~40 seedlings coming from 4 different MS plates. Frozen plant material was grounded in an eppendorf tube using a mini pestle. RNA was extracted using RNeasy Plant Mini kit (QIAGEN cat.74904), following the manufacturer instructions (QIAGEN, Hilden, Germany). The RNA samples were DNase treated (Recombinant DNase I, Takara Biotechnology, Dalian, China) and subsequently cleaned by column using RNeasy Plant Mini kit (QIAGEN, Hilden, Germany).
2013-09-01 | GSE43883 | GEO
Project description:Manipulation of the ubiquitin proteasome system (UPS) is emerging as a common theme in viral pathogenesis. Some viruses have been shown to encode functional homologs of UPS enzymes, suggesting that a systematic identification of these products may provide new insights into virus-host cell interactions. Ubiquitin-specific proteases, collectively known as deubiquitinating enzymes (DUBs), regulate the activity of the UPS by hydrolyzing ubiquitin peptide or isopeptide bonds. The prediction of viral DUBs based on sequence similarity with known enzymes is hampered by the diversity of viral genomes. In this study sequence alignments, pattern searches, and hidden Markov models were developed for the conserved C- and H-boxes of the known DUB families and used to search the open reading frames (ORFs) of Epstein-Barr virus (EBV), a large gammaherpesvirus that has been implicated in the pathogenesis of a broad spectrum of human malignancies of lymphoid and epithelial cell origin. The searches identified a limited number of EBV ORFs that contain putative DUB catalytic domains. DUB activity was confirmed by functional assays and mutation analysis for three high scoring candidates, supporting the usefulness of this bioinformatics approach in predicting distant homologues of cellular enzymes.
| S-EPMC2573217 | biostudies-literature
Project description:Dysfunction or dysregulation of the ubiquitin proteasome system (UPS) is closely related to tumorigenesis and the development of multiple cancers. Targeting the UPS provides a new anticancer therapeutic strategy, but clinically available UPS-targeted inhibitors, including lenalidomide and bortezomib, are limited to treat solid tumors. Under physiological conditions, deubiquitinases or deubiquitinating enzymes (DUBs) play vital roles in the UPS by removing ubiquitin from substrate proteins and regulating their proteasomal degradation and sub-localization, thus maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis. The aberrant expression or function of DUBs generally leads to the occurrence and progression of a series of disorders, including malignant tumors. Therefore, targeting DUBs is a novel anticancer therapeutic strategy. Ubiquitin-specific proteases (USPs) are the largest subfamily of DUBs which have attracted considerable interest as anticancer targets. Most of USPs are abnormally activated or expressed in a variety of malignant tumors or in the tumor microenvironment, making them ideal anticancer target candidates, which indicates that USPs inhibitors may be a class of potential anticancer therapeutic agents. However, there are no relevant inhibitors targeting USPs have entered clinical trial so far. In this review, we will summarize the roles and mechanisms of USPs in malignant transformation and progression as well as recent advances of small-molecule inhibitors targeting USPs.
| S-EPMC6171565 | biostudies-literature
Project description:Ubiquitination and deubiquitination have emerged as critical regulatory processes in the virus-triggered type I interferon (IFN) induction pathway. In this study, we carried out a targeted siRNA screen of 54 ubiquitin-specific proteases (USPs) and identified USP25 as a negative regulator of the virus-triggered type I IFN signaling pathway. Overexpression of USP25 inhibited virus-induced activation of IFN-?, interferon regulation factor 3 (IRF3) and nuclear factor-kappa B (NF-?B), as well as the phosphorylation of IRF3 and NF-?B subunit p65. Furthermore, Knockdown of USP25 potentiated virus-induced induction of the IFN-?. In addition, detailed analysis demonstrated that USP25 cleaved lysine 48- and lysine 63-linked polyubiquitin chains in vitro and in vivo, and its deubiquitinating enzyme (DUB) activity, were dependent on a cysteine residue (Cys178) and a histidine residue (His607). USP25 mutants lacking DUB activity lost the ability to block virus-induced type I IFN to some degree. Mechanistically, USP25 deubiquitinated retinoic acid-inducible gene I (RIG-I), tumornecrosis factor (TNF) receptor-associated factor 2 (TRAF2), and TRAF6 to inhibit RIG-I-like receptor-mediated IFN signaling. Our findings suggest that USP25 is a novel DUB negatively regulating virus-induced type I IFN production.
| S-EPMC3832446 | biostudies-literature
Project description:BackgroundThe ubiquitination process can be reversed by deubiquitinating enzymes (DUBs). These proteases are involved in ubiquitin processing, in the recovery of modified ubiquitin trapped in inactive forms, and in the recycling of ubiquitin monomers from polyubiquitinated chains. The diversity of DUB functions is illustrated by their number and variety of their catalytic domains with specific 3D architectures. DUBs can be divided into five subclasses: ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs or UBPs), ovarian tumour proteases (OTUs), Machado-Joseph disease proteases (MJDs) and JAB1/MPN/Mov34 metalloenzymes (JAMMs).MethodsConsidering the role that the ubiquitin-proteasome system has been shown to play during the development of Schistosoma mansoni, our main goal was to identify and characterize SmUSPs. Here, we showed the identification of putative ubiquitin-specific proteases using bioinformatic approaches. We also evaluated the gene expression profile of representative USP family members using qRT-PCR.ResultsWe reported 17 USP family members in S. mansoni that present a conservation of UCH domains. Furthermore, the putative SmUSP transcripts analysed were detected in all investigated stages, showing distinct expression during S. mansoni development. The SmUSPs exhibiting high expression profiles were SmUSP7, SmUSP8, SmUSP9x and SmUSP24.ConclusionS. mansoni USPs showed changes in expression levels for different life cycle stages indicating their involvement in cellular processes required for S. mansoni development. These data will serve as a basis for future functional studies of USPs in this parasite.
| S-EPMC4485857 | biostudies-literature
Project description:Ubiquitin signaling mechanisms play fundamental roles in the cell-intrinsic control of neuronal morphogenesis and connectivity in the brain. However, whereas specific ubiquitin ligases have been implicated in key steps of neural circuit assembly, the roles of ubiquitin-specific proteases (USPs) in the establishment of neuronal connectivity have remained unexplored. Here, we report a comprehensive analysis of USP family members in granule neuron morphogenesis and positioning in the rodent cerebellum. We identify a set of 32 USPs that are expressed in granule neurons. We also characterize the subcellular localization of the 32 USPs in granule neurons using a library of expression plasmids encoding GFP-USPs. In RNAi screens of the 32 neuronally expressed USPs, we uncover novel functions for USP1, USP4, and USP20 in the morphogenesis of granule neuron dendrites and axons and we identify a requirement for USP30 and USP33 in granule neuron migration in the rodent cerebellar cortex in vivo. These studies reveal that specific USPs with distinct spatial localizations harbor key functions in the control of neuronal morphogenesis and positioning in the mammalian cerebellum, with important implications for our understanding of the cell-intrinsic mechanisms that govern neural circuit assembly in the brain.
| S-EPMC4301861 | biostudies-literature
Project description:Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.
| S-EPMC4958508 | biostudies-literature
Project description:The Lon protease selectively degrades abnormal proteins or certain normal proteins in response to environmental and cellular conditions in many prokaryotic and eukaryotic organisms. However, the mechanism(s) behind the substrate selection of normal proteins remains largely unknown. In this study, we identified 10 new substrates of F. tularensis Lon from a total of 21 candidate substrates identified in our previous work, the largest number of novel Lon substrates from a single study. Cross-species degradation of these and other known Lon substrates revealed that human Lon is unable to degrade many bacterial Lon substrates, suggestive of a "organism-adapted" substrate selection mechanism for the natural Lon variants. However, individually replacing the N, A, and P domains of human Lon with the counterparts of bacterial Lon did not enable the human protease to degrade the same bacterial Lon substrates. This result showed that the "organism-adapted" substrate selection depends on multiple domains of the Lon proteases. Further in vitro proteolysis and mass spectrometry analysis revealed a similar substrate cleavage pattern between the bacterial and human Lon variants, which was exemplified by predominant representation of leucine, alanine, and other hydrophobic amino acids at the P(-1) site within the substrates. These observations suggest that the Lon proteases select their substrates at least in part by fine structural matching with the proteins in the same organisms.
| S-EPMC6098112 | biostudies-literature