1,122 results match your criteria polyubiquitin chains

Conformational stabilization of optineurin by the dynamic interaction of linear polyubiquitin.

Biochem Biophys Res Commun 2021 May 2;559:203-209. Epub 2021 May 2.

Laboratory of Molecular Cell Dynamics, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.

Optineurin produces intracellular multi-functions involving autophagy, vesicular trafficking, and negative regulation of inflammation signaling through interaction with various proteins such as ATG8/LC3, Rab8, and polyubiquitin. Optineurin is a component of cytoplasmic inclusion bodies (IBs) in motor neurons from amyotrophic lateral sclerosis (ALS), and its mutation E478G, has been identified in patients with ALS. However, the mechanism by which polyubiquitin binding modulates the interaction partners of OPTN and ALS-associated IB formation is still unclear. Read More

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Primary restriction of S-RNase cytotoxicity by a stepwise ubiquitination and degradation pathway in Petunia hybrida.

New Phytol 2021 May 1. Epub 2021 May 1.

State Key Laboratory of Plant Cell and Chromosome Engineering, Institute of Genetics and Developmental Biology, The Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, 100101, China.

In self-incompatible Petunia species, the pistil S-RNase acts as cytotoxin to inhibit self-pollination but is polyubiquitinated by the pollen-specific non-self S-locus F-box (SLF) proteins and subsequently degraded by the ubiquitin-proteasome system (UPS), allowing cross-pollination. However, it remains unclear how S-RNase is restricted by the UPS. Using biochemical analyses, we first show that Petunia hybrida S -RNase is largely ubiquitinated by K48-linked polyubiquitin chains at three regions, R I, II and III. Read More

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Conformational space sampled by domain reorientation of linear diubiquitin reflected in its binding mode for target proteins.

Chemphyschem 2021 Apr 29. Epub 2021 Apr 29.

Kyoto University: Kyoto Daigaku, Department of biophysics, Kitashirakawa-oiwake, Sakyo-ku, 606-8502, Kyoto, JAPAN.

Linear polyubiquitin chains regulate diverse signaling proteins, in which the chains adopt various conformations to recognize different target proteins. Thus, the structural plasticity of the chains plays an important role in controlling the binding events. Here, paramagnetic NMR spectroscopy is employed to explore the conformational space sampled by linear diubiquitin, a minimal unit of linear polyubiquitin, in its free state. Read More

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The Ubiquitin-Specific Protease TNI/UBP14 Functions in Ubiquitin Recycling and Affects Auxin Response.

Plant Physiol 2020 Nov;184(3):1499-1513

Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India.

The ubiquitin-mediated proteasomal pathway regulates diverse cellular processes in plants by rapidly degrading target proteins, including the repressors of hormone signaling. Though ubiquitin proteases play a key role in this process by cleaving polyubiquitin chains to monomers, their function has not been studied in detail by mutational analysis. Here, we show that mutation in TARANI/UBIQUITIN-SPECIFIC PROTEASE14 (TNI/UBP14) leads to reduced auxin response and widespread auxin-related phenotypic defects in Arabidopsis (Arabidopsis thaliana). Read More

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November 2020

The deubiquitinase TRABID stabilizes the K29/K48-specific E3 ubiquitin ligase HECTD1.

J Biol Chem 2020 12 30;296:100246. Epub 2020 Dec 30.

Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom. Electronic address:

Ubiquitin is a versatile posttranslational modification, which is covalently attached to protein targets either as a single moiety or as a ubiquitin chain. In contrast to K48 and K63-linked chains, which have been extensively studied, the regulation and function of most atypical ubiquitin chains are only starting to emerge. The deubiquitinase TRABID/ZRANB1 is tuned for the recognition and cleavage of K29 and K33-linked chains. Read More

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December 2020

Acetylated Ubiquitin Modulates the Catalytic Activity of the E1 Enzyme Uba1.

Biochemistry 2021 Apr 13;60(16):1276-1285. Epub 2021 Apr 13.

Department of Biochemistry, Western University, London, Ontario N6A 5C1, Canada.

Ubiquitin (Ub) signaling requires the covalent passage of Ub among E1, E2, and E3 enzymes. The choice of E2 and E3 enzymes combined with multiple rounds of the cascade leads to the formation of polyubiquitin chains linked through any one of the seven lysines on Ub. The linkage type and length act as a signal to trigger important cellular processes such as protein degradation or the DNA damage response. Read More

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Mdm2-Mediated Downmodulation of GRK2 Restricts Centrosome Separation for Proper Chromosome Congression.

Cells 2021 Mar 25;10(4). Epub 2021 Mar 25.

Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049 Madrid, Spain.

The timing of centrosome separation and the distance moved apart influence the formation of the bipolar spindle, affecting chromosome stability. Epidermal growth factor receptor (EGFR) signaling induces early centrosome separation through downstream G protein-coupled receptor kinase GRK2, which phosphorylates the Hippo pathway component MST2 (Mammalian STE20-like protein kinase 2), in turn allowing NIMA kinase Nek2A activation for centrosomal linker disassembly. However, the mechanisms that counterbalance centrosome disjunction and separation remain poorly understood. Read More

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Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention.

Cancers (Basel) 2021 Mar 25;13(7). Epub 2021 Mar 25.

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.

The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Read More

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OTUD1 Regulates Antifungal Innate Immunity through Deubiquitination of CARD9.

J Immunol 2021 Apr 31;206(8):1832-1843. Epub 2021 Mar 31.

Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University, 250012 Jinan, Shandong, People's Republic of China;

CARD9 is an essential adaptor protein in antifungal innate immunity mediated by C-type lectin receptors. The activity of CARD9 is critically regulated by ubiquitination; however, the deubiquitinases involved in CARD9 regulation remain incompletely understood. In this study, we identified ovarian tumor deubiquitinase 1 (OTUD1) as an essential regulator of CARD9. Read More

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Down-Regulation of LOC645166 in T Cells of Ankylosing Spondylitis Patients Promotes the NF-κB Signaling Decreasingly Blocking Recruitment of the IKK Complex to K63-Linked Polyubiquitin Chains.

Front Immunol 2021 25;12:591706. Epub 2021 Feb 25.

Department of Biomedical Sciences, National Chung Cheng University, Chiayi, Taiwan.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the spine. AS is highly associated with the expression of HLA-B27. Up to 95% AS patients are HLA-B27-positive. Read More

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February 2021

In-depth characterization of ubiquitin turnover in mammalian cells by fluorescence tracking.

Cell Chem Biol 2021 Mar 2. Epub 2021 Mar 2.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 Moscow, Russian Federation; Lomonosov Moscow State University, Leninskie Gory, 119991 Moscow, Russian Federation. Electronic address:

Despite almost 40 years having passed from the initial discovery of ubiquitin (Ub), fundamental questions related to its intracellular metabolism are still enigmatic. Here we utilized fluorescent tracking for monitoring ubiquitin turnover in mammalian cells, resulting in obtaining qualitatively new data. In the present study we report (1) short Ub half-life estimated as 4 h; (2) for a median of six Ub molecules per substrate as a dynamic equilibrium between Ub ligases and deubiquitinated enzymes (DUBs); (3) loss on average of one Ub molecule per four acts of engagement of polyubiquitinated substrate by the proteasome; (4) direct correlation between incorporation of Ub into the distinct type of chains and Ub half-life; and (5) critical influence of the single lysine residue K27 on the stability of the whole Ub molecule. Read More

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The high stability of the three-helix bundle UBA domain of p62 protein as revealed by molecular dynamics simulations.

J Mol Model 2021 Mar 5;27(4):102. Epub 2021 Mar 5.

Departamento de Física, FFCLRP, Universidade de São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, 14040-901, SP, Brazil.

The ubiquitin-associated (UBA) domain is an important motif in the modulation of many molecular functionalities. It has been mainly associated with ubiquitin-mediated proteolysis, a multistep mechanism in which undesirable proteins are tagged with polyubiquitin chains for degradation in the proteasome complex. Comparison among UBA domains reveals a quite small structural variability, displaying an overall fold with a tightly packed three-helix bundle, and a common conserved hydrophobic patch on their surface that is important for ubiquitin binding. Read More

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A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma.

Oncogene 2021 Apr 3;40(13):2367-2381. Epub 2021 Mar 3.

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.

Histone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, HDAC inhibitors are much more effective in combination with other anti-cancer agents. To identify novel compounds which act synergistically with HDAC inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed a cell-based, high-throughput drug screen of 10,560 small molecule compounds from a drug-like diversity library and identified a small molecule compound (SE486-11) which synergistically enhanced the cytotoxic effects of SAHA. Read More

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Polyubiquitin and ubiquitin-like signals share common recognition sites on proteasomal subunit Rpn1.

J Biol Chem 2021 Feb 19:100450. Epub 2021 Feb 19.

Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, MD 20742, USA. Electronic address:

Proteasome-mediated substrate degradation is an essential process that relies on the coordinated actions of ubiquitin (Ub), shuttle proteins containing Ub-like (UBL) domains, and the proteasome. Proteinaceous substrates are tagged with polyUb and shuttle proteins and these signals are then recognized by the proteasome, which subsequently degrades the substrate. To date, three proteasomal receptors have been identified, as well as multiple shuttle proteins and numerous types of polyUb chains that signal for degradation. Read More

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February 2021

The UBA domain of conjugating enzyme Ubc1/Ube2K facilitates assembly of K48/K63-branched ubiquitin chains.

EMBO J 2021 Mar 12;40(6):e106094. Epub 2021 Feb 12.

Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin-Buch, Germany.

The assembly of a specific polymeric ubiquitin chain on a target protein is a key event in the regulation of numerous cellular processes. Yet, the mechanisms that govern the selective synthesis of particular polyubiquitin signals remain enigmatic. The homologous ubiquitin-conjugating (E2) enzymes Ubc1 (budding yeast) and Ube2K (mammals) exclusively generate polyubiquitin linked through lysine 48 (K48). Read More

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TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains.

Mol Cell 2021 04 9;81(7):1411-1424.e7. Epub 2021 Feb 9.

Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan; School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan; Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. Electronic address:

Targeted protein degradation is an emerging therapeutic paradigm. Small-molecule degraders such as proteolysis-targeting chimeras (PROTACs) induce the degradation of neo-substrates by hijacking E3 ubiquitin ligases. Although ubiquitylation of endogenous substrates has been extensively studied, the mechanism underlying forced degradation of neo-substrates is less well understood. Read More

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MIND bomb 2 prevents RIPK1 kinase activity-dependent and -independent apoptosis through ubiquitylation of cFLIP.

Commun Biol 2021 Jan 19;4(1):80. Epub 2021 Jan 19.

Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan.

Mind bomb 2 (MIB2) is an E3 ligase involved in Notch signalling and attenuates TNF-induced apoptosis through ubiquitylation of receptor-interacting protein kinase 1 (RIPK1) and cylindromatosis. Here we show that MIB2 bound and conjugated K48- and K63-linked polyubiquitin chains to a long-form of cellular FLICE-inhibitory protein (cFLIP), a catalytically inactive homologue of caspase 8. Deletion of MIB2 did not impair the TNF-induced complex I formation that mediates NF-κB activation but significantly enhanced formation of cytosolic death-inducing signalling complex II. Read More

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January 2021

The role of E3 ubiquitin ligases in the development and progression of glioblastoma.

Cell Death Differ 2021 Feb 11;28(2):522-537. Epub 2021 Jan 11.

Department of Oncology, Medical Research Council Institute for Radiation Oncology, University of Oxford, Oxford, UK.

Despite recent advances in our understanding of the disease, glioblastoma (GB) continues to have limited treatment options and carries a dismal prognosis for patients. Efforts to stratify this heterogeneous malignancy using molecular classifiers identified frequent alterations in targetable proteins belonging to several pathways including the receptor tyrosine kinase (RTK) and mitogen-activated protein kinase (MAPK) signalling pathways. However, these findings have failed to improve clinical outcomes for patients. Read More

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February 2021

CHIP promotes Wnt signaling and regulates Arc stability by recruiting and polyubiquitinating LEF1 or Arc.

Cell Death Discov 2021 Jan 11;7(1). Epub 2021 Jan 11.

School of LifeSciences, Zhengzhou University, Zhengzhou, Henan, China.

The carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, participates in many cellular processes such as protein degradation, trafficking, autophagy, apoptosis, and multiple signaling transductions. The mutant of CHIP (p.T246M) causes the spinocerebellar autosomal recessive 16 (SCAR16), a neurodegenerative disease characterized by spinocerebellar atrophy. Read More

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January 2021

[Intermolecular interaction-based ubiquitin-proteasome system-targeting drug discovery].

Nihon Yakurigaku Zasshi 2021 ;156(1):9-12

Interprotein Corporation.

We review recent advances of Ubiquitin-Proteasome System (UPS)-based research and development with increased focus as drug discovery approaches and introduce applications of chimera-type small molecule compounds (SNIPER/PROTAC) that selectively promote degradation of a drug target protein. UPS makes the point (polyubiquitin chain) of targeting protein as a substrate and has a property that degrade the target protein with proteasome. Protein knockout technologies degrade the drug target protein by apply this protein degrading system. Read More

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January 2021

African Swine Fever Virus Ubiquitin-Conjugating Enzyme Interacts With Host Translation Machinery to Regulate the Host Protein Synthesis.

Front Microbiol 2020 15;11:622907. Epub 2020 Dec 15.

Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Madrid, Spain.

African Swine Fever virus (ASFV) causes one of the most relevant emerging diseases affecting swine, now extended through three continents. The virus has a large coding capacity to deploy an arsenal of molecules antagonizing the host functions. In the present work, we have studied the only known E2 viral-conjugating enzyme, UBCv1 that is encoded by the gene of ASFV. Read More

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December 2020

K63-linked ubiquitylation induces global sequestration of mitochondria.

Sci Rep 2020 12 18;10(1):22334. Epub 2020 Dec 18.

Department of Cell and Molecular Biology, Biomedicum, Karolinska Institutet, Solnavägen 9, 17177, Stockholm, Sweden.

Even though K63-linked polyubiquitin chains do not target proteins for proteasomal degradation, they play nevertheless a complementary protective role in maintaining protein homeostasis by directing malfunctioning proteins and organelles to inclusion bodies or autophagosomes. A paradigm for this process is the sequestration and autophagic degradation of dysfunctional mitochondria. Although studies have shown that K63-ubiquitylation of mitochondrial proteins by the ubiquitin ligase Parkin is important in this process, it is presently not clear if this modification also suffices to initiate this cascade of events. Read More

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December 2020

Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance.

J Exp Med 2021 Mar;218(3)

Department of Pathology, Yale School of Medicine, New Haven, CT.

White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Read More

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Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors.

Bioorg Med Chem 2021 01 9;29:115867. Epub 2020 Nov 9.

National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address:

A series of non-covalent piperidine-containing peptidyl derivatives with various substituents at side chains of different residues were designed, synthesized and evaluated as proteasome inhibitors. After proteasome inhibitory evaluations of all the synthesized target compounds, selected ones were tested for their anti-proliferation activities against three multiple myeloma (MM) cell lines. 8 analogues displayed more potent activities than carfilzomib, and the most promising compound 24 showed IC values of 0. Read More

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January 2021

UFBP1, a key component in ufmylation, enhances drug sensitivity by promoting proteasomal degradation of oxidative stress-response transcription factor Nrf2.

Oncogene 2021 Jan 20;40(3):647-662. Epub 2020 Nov 20.

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, China.

The key component in the UFM1 conjugation system, UFM1-binding and PCI domain-containing protein 1 (UFBP1), regulates many biological processes. Recently it has been shown that low UFBP1 protein level is associated with the worse outcome of gastric cancer patients. However, how it responses to the sensitivity of gastric cancer to chemotherapy drugs and the underlying molecular mechanism remain elusive. Read More

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January 2021

Antiproliferative activity exerted by tricyclohexylphosphanegold(I) n-mercaptobenzoate against MCF-7 and A2780 cell lines: the role of p53 signaling pathways.

Biometals 2021 Feb 16;34(1):141-160. Epub 2020 Nov 16.

Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.

Based on the recent studies depicting the potential of heterometallic gold complexes as potent antiproliferative agents, herein we first reported the preliminary mechanistic data on the in-vitro antiproliferative activity of tricyclohexylphosphanegold(I) n-mercaptobenzoate, CyPAu(n-MBA) where n = 2 (1), 3 (2) and 4 (3), and MBA = mercaptobenzoic acid, treated using MCF-7 breast cancer and A2780 ovarian cancer cells, respectively. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to assess the cytotoxicity of both cancer cells treated with 1-3, respectively. The IC of 1-3 were applied to the subsequent assays including cell invasion and thioredoxin reductase (TrxR) as well as ubiquitin activities specifically on Lys48 and Lys63-linked polyubiquitin chains via flowcytometric analysis. Read More

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February 2021

Ubiquitin chains earmark GPCRs for BBSome-mediated removal from cilia.

J Cell Biol 2020 12;219(12)

Department of Ophthalmology, University of California, San Francisco, San Francisco, CA.

Regulated trafficking of G protein-coupled receptors (GPCRs) controls cilium-based signaling pathways. β-Arrestin, a molecular sensor of activated GPCRs, and the BBSome, a complex of Bardet-Biedl syndrome (BBS) proteins, are required for the signal-dependent exit of ciliary GPCRs, but the functional interplay between β-arrestin and the BBSome remains elusive. Here we find that, upon activation, ciliary GPCRs become tagged with ubiquitin chains comprising K63 linkages (UbK63) in a β-arrestin-dependent manner before BBSome-mediated exit. Read More

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December 2020

Bacterial OTU deubiquitinases regulate substrate ubiquitination upon Legionella infection.

Elife 2020 11 13;9. Epub 2020 Nov 13.

Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.

causes a severe pneumonia known as Legionnaires' disease. During the infection, Legionella injects more than 300 effector proteins into host cells. Among them are enzymes involved in altering the host-ubiquitination system. Read More

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November 2020

The N-terminal cysteine protease domain of rice stripe tenuivirus Pc1 possesses deubiquitinating enzyme activity.

Virus Genes 2021 Feb 4;57(1):117-120. Epub 2020 Nov 4.

College of Bioscience and Biotechnology, Yangzhou University, No. 48 Wenhui Road East, Yangzhou, 225009, People's Republic of China.

Virus encoded deubiquitinating enzyme (DUB) plays important roles in viral replication and the regulation of host innate immunity. Bioinformatics-based analysis revealed the presence of an ovarian tumor (OTU) protease domain in the N terminus of rice stripe tenuivirus (RSV) Pc1. Many viral OTU domains have been reported to possess DUB activity, which suggests that RSV OTU probably also have DUB activity. Read More

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February 2021

Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex.

PLoS Pathog 2020 10 27;16(10):e1008784. Epub 2020 Oct 27.

York Biomedical Research Institute and Department of Biology, University of York, United Kingdom.

Post-translational modifications such as ubiquitination are important for orchestrating the cellular transformations that occur as the Leishmania parasite differentiates between its main morphological forms, the promastigote and amastigote. 2 E1 ubiquitin-activating (E1), 13 E2 ubiquitin-conjugating (E2), 79 E3 ubiquitin ligase (E3) and 20 deubiquitinating cysteine peptidase (DUB) genes can be identified in the Leishmania mexicana genome but, currently, little is known about the role of E1, E2 and E3 enzymes in this parasite. Bar-seq analysis of 23 E1, E2 and HECT/RBR E3 null mutants generated in promastigotes using CRISPR-Cas9 revealed numerous loss-of-fitness phenotypes in promastigote to amastigote differentiation and mammalian infection. Read More

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October 2020