Dissertations / Theses on the topic 'Ubiquitin'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Ubiquitin.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
Sekiyama, Naotaka. "STRUCTURAL ANALYSIS OF UBIQUITIN AND UBIQUITIN-LIKE PROTEIN RECEPTORS." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/120884.
Full textBraxton, Courtney N. "The progress on mapping ubiquitin signaling using photocrosslinking mono and di-ubiquitin probes and other ubiquitin moieties." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5382.
Full textHaririnia, Aydin. "Molecular interactions of ubiquitin and polyubiquitin with ubiquitin binding domains." College Park, Md. : University of Maryland, 2007. http://hdl.handle.net/1903/7627.
Full textThesis research directed by: Dept. of Chemistry and Biochemistry. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
Lange, Anja. "Structural characterization of the interaction of the Stam2's ubiquitin binding domains with ubiquitin chains by NMR : Cooperativity or not, that is the question !" Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10308.
Full textFrom the discovery of ubiquitin and its function as signal for proteasomal degradation over 20 years ago to this days, it became evident that ubiquitin is a universal signal in eukaryotic cells. Ubiquitin in its different forms is involved in many versatile cellular processes. Knowing that the ubiquitin signal is differently translated, depending on its occurrences as mono-ubiquitin or poly-ubiquitin, raises the question: how do cells distinguish between the different occurrences of ubiquitin and translate it into the proper response? Proteins interacting with ubiquitin contain so called ubiquitin binding domains (UBDs), whereas the affinities to ubiquitin vary from a few _M to mM. So far only three (K63, K48 and linear chains) out of the eight possible chain-linkages can be produced in sufficient amounts to characterize their interaction with UBDs. K48- and K63- linked ubiquitin chains regulate different cellular events and need to be recognized by different proteins. Thus, it is of prime importance to characterize the binding of different UBDs to these two kinds of ubiquitin chains, as it can give important clues related to the general mechanism of chain discrimination by ubiquitin adapter proteins. Some isolated UBDs exhibit a preference for one chain linkage type over the other, whereas others do not discriminate between mono-ubiquitin or K63- and K48-linked chains. Interestingly, many ubiquitin adapter proteins harbor more than one UBD. STAM2 is a ubiquitin adapter protein, that is involved in endosomal receptor sorting and supposed to preferentially bind mono-ubiquitin and K63- over K48-linked ubiquitin. STAM2 contains two UBDs (a VHS and UIM domain) that were shown to bind to ubiquitin . The current manuscript shows that STAM2’s SH3 domain binds ubiquitin as well. To understand the function of the sequential arrangement of three UBDs in one protein, first binding of the individual VHS and UIM domains to monoubiquitin as well as K48- and K63-linked di-ubiquitin was investigated. This work shows, that the VHS domain displays a different mode of binding for K63- and K48-linked diubiquitin. In spite of the fact, that the apparent Kd for both chains is the same, only one VHS domain can bind to K48-linked di-ubiquitin chains (with a preference for the distal domain), whereas K63-linked di-ubiquitin can accommodate two VHS domains at a time. Since no conclusion can be drawn with respect to the apparent Kds, the different binding modes might gain more impact in consideration of the ensemble of three UBDs. Results presented in this manuscript, based on a construct containing the VHS and UIM domain, show that binding to K63- but not K48-linked di-ubiquitin is cooperative
Pirim, Ibrahim. "Ubiquitin and neurogenerative diseases." Thesis, University of Nottingham, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335277.
Full textDeschutter, Julie. "Identification de la monoubiquitination de la protéine SHIP2 et caractérisation des mécanismes régulateurs associés." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/241308.
Full textDepaux, Arnaud. "Régulation des complexes d'ubiquitinylation et de sumoylation par la ligase E3 hSIAH2." Paris 7, 2006. http://www.theses.fr/2006PA077094.
Full textAfter synthesis, proteins are targeted to post-translational modifications such as acetylation, phosphorylation or ubiquitination. These mechanisms regulate their function, stability, localization or interaction with partners. Modification process by ubiquitin or sumo named ubiquitination or sumoylation respectively involve complexes with similar organization but compose of different enzymes. Their organization relies on Sumo or ubiquitin activating El enzyme, transferring E2-ligase and E3-ligase or sub-complex conferring the substrate specific récognition. El-ligase is unique for each complex, whereas E2 and E3-ligases are multiple. Among E3-ligase families, RING Finger protein family only has been involved in both modifications complexes. Two human homologs of Drosophila Seven In Absentia (hSIAHl et hSIAH2), belong to RING Finger E3-ligase family. In a yeast two hybrid assay, we have identified new SIAH interacting proteins. Their characterization has been the purpose of my PhD project. We have characterized partners implicated in both ubiquitination (ubiquitin, Ubc5 or hSIAH) and sumoylation (Sumo, Ubc9 and PIAS) pathways. In a first attempt, I have demonstrated that hSIAH proteins can form homo- or hetero-dimers. Dimerization régulates their stability via a proteasome dependent degradation. I have also demonstrated that hSIAH2 catalyzes the proteasome dependent degradation of PIAS1, a sumo E3-ligase. Altogether this study evidences an important rôle for hSIAH2 in the regulation of the stability of ubiquitination and sumolation complexes
Bazirgan, Omar Al-Kasim. "Functional analysis of the ubiquitin ligase Hrd1p with the ubiquitin-conjugating enzyme Ubc7p." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3246079.
Full textTitle from first page of PDF file (viewed March 9, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
Rumsby, Ellen Louise. "Regulation of the cell division cycle by ubiquitin and ubiquitin-like modifications in yeast." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2938.
Full textSouza, Letícia Martins Ignácio de 1987. "Sistema ubiquitina-proteassoma no hipotálamo : implicações para a gênese da obesidade." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310374.
Full textTese (Doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-22T00:15:51Z (GMT). No. of bitstreams: 1 Souza_LeticiaMartinsIgnaciode_D.pdf: 4083691 bytes, checksum: 4627dc93519577a00d2747b36d1a406f (MD5) Previous issue date: 2013
Resumo: Dentre os fatores ambientais que contribuem para o desenvolvimento de obesidade, o consumo de dietas ricas em ácidos graxos saturados desempenha o papel mais importante. Estudos recentes realizados por vários grupos, inclusive o nosso, revelam que ácidos graxos saturados presentes na dieta levam ao desenvolvimento de resistência hipotalâmica à ação dos hormônios leptina e insulina, fenômeno este fundamental para que ocorra a quebra no equilíbrio entre ingestão e gasto calórico. Até o momento caracterizaram-se dois mecanismos moleculares potencialmente envolvidos na iniciação do processo que resulta na disfunção hipotalâmica na obesidade, a ativação de TLR4 e a indução de estresse de retículo endoplasmático, ambos levando a uma resposta inflamatória local e, eventualmente, a apoptose neuronal. Estudos recentes têm revelado que frente a situações que oferecem risco de dano celular, ativa-se um mecanismo de controle de tráfico e degradação protéica chamado sistema ubiquitina-proteassoma (UPS). O acúmulo de agregados protéicos positivos para ubiquitina pode gerar toxicidade celular e regular a plasticidade neuronal. Também a modulação de componentes do UPS pode gerar neurodegeneração hipotalâmica e fenótipo obeso em animais experimentais. Neste estudo aventamos a hipótese que durante períodos prolongados de obesidade a ativação anômala do UPS contribuiria para a perpetuação do quadro de obesidade. De fato, os resultados obtidos revelam que roedores com predisposição para a obesidade induzida por dieta mantém, a princípio, a capacidade de regular adequadamente a UPS no hipotálamo. Com o passar do tempo esta capacidade é perdida resultando numa maior dificuldade para perda de peso frente à redução do aporte calórico. Roedores com mutações que os protegem da inflamação, não apresentam distúrbio funcional do UPS quando expostos a dieta rica em ácidos graxos e, são também protegidos da obesidade. Portanto, o defeito funcional do UPS no hipotálamo no curso de obesidade prolongada, constitui-se num fator importante contribuindo para a refratariedade ao tratamento e perpetuação da doença
Abstract: The consumption of high-fat diets, especially those rich in saturated fatty acids, plays the most important role in the development of obesity. Recent studies by several groups, including ours, have shown that dietary long-chain saturated fatty acids lead to the development of hypothalamic resistance to leptin and insulin, an important condition contributing for breaking of the balance between caloric intake and energy expenditure. Two molecular mechanisms are currently known to play a triggering role in this process; activation of TLR4 and endoplasmic reticulum stress, both leading to local inflammation and eventually apoptosis of neurons. The ubiquitin-proteasome system (UPS) plays an important role in the control of protein recycling in the cell. The accumulation of ubiquitin-positive protein aggregates can cause cell toxicity and regulate neuronal plasticity. Also the modulation or differential activation of UPS can produce hypothalamic neurodegeneration and obese phenotype in experimental animals. Here, we hypothesized that under prolonged diet-induced obesity, a defect in the UPS in the hypothalamus could contribute for the defective control of energy homeostasis leading to the refractoriness of obesity to caloric restriction. In fact in an obesity-prone rodent strain, prolonged, but not short-term obesity was accompanied by functional abnormality of the UPS in the hypothalamus. In mutants protected from inflammation, resistance to diet-induced obesity was accompanied by stability of the UPS in the hypothalamus. Thus, defect of the UPS in the hypothalamus, during prolonged obesity is an important factor contributing the refractoriness of obesity to caloric restriction
Doutorado
Biologia Estrutural, Celular, Molecular e do Desenvolvimento
Doutora em Fisiopatologia Médica
Schick, Martin Christopher. "High pressure NMR of ubiquitin /." Zürich, 1998. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=12586.
Full textTsirigotis, Maria. "Mutational analysis of mammalian ubiquitin." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/29267.
Full textLigr, Martin. "Ubiquitin metabolism in Chlamydomonas reinhardtii." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1995. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/MQ33407.pdf.
Full textBoehringer, Jonas. "Ubiquitin recognition by the proteasome." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:036151d9-5062-4ffe-a1ef-a58e1b020680.
Full textShi, Yuan. "Ubiquitin Recognition by the Proteasome." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070024.
Full textYe, Yu. "Targeting ubiquitin chains with deubiquitinases." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610783.
Full textWilken, Jill. "Synthesis and structure of ubiquitin." Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/13236.
Full textGreen, Jeremy. "Towards the synthesis of ubiquitin." Thesis, University of Edinburgh, 1987. http://hdl.handle.net/1842/14941.
Full textOughtred, Rose W. "Characterization of ubiquitin-protein ligases in the testis interacting with the UBC4UBC5 ubiquitin-conjugating enzymes." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36825.
Full textPreviously, rat UBC4 isoforms homologous to S. cerevisiae UBC4/UBC5 were cloned and characterized (Wing and Jain, 1995) (Wing et al., 1996). The UBC4-1 isoform is highly expressed in the testis, and the UBC4-testis isoform is induced in round spermatids. This thesis describes the identification and characterization of E3s interacting with these UBC4 isoforms expressed in the rat testis.
First, the isolation and characterization of a novel E3 from rat testis extracts, E3Histone, is described. E3Histone mediates conjugation of ubiquitin to histones in a UBC4-dependent manner. Interestingly, E3Histone was immunodepleted by antibodies against Cdc27, a subunit of the a&barbelow;naphase-p&barbelow;romoting c&barbelow;omplex (APC), an E3 which plays a critical role in the regulation of the cell cycle. However, E3Histone and the APC are distinct complexes. Gel filtration resolved the 600 kDa E3Histone from the 1500 kDa APC. E3Histone interacts preferentially with UBC4, whereas the APC interacts preferentially with UbcH10 and shows specificity for the substrate cyclin. E3Histone and the APC may be members of a newly-recognized family of combinatorial E3s that share some common core subunits, such as CDC27, yet possess distinct subunits that confer upon them their respective E2 and substrate specificities. In addition, E3Histone activity was detected in extracts from various purified germ cells. Induction of UBC4 may lead to the increased ubiquitination of histories and together with E3 Histone may play a role in the chromatin condensation that occurs during spermatid maturation.
Secondly, the characterization of a HECT domain E3, Rat100, is described. UBC4-1 and UBC4-testis were found to transfer ubiquitin to Rat100 in vitro. Immunoblotting showed that Rat100 has a molecular weight of 300 kDa, and that the developmental and cell-specific expression of Rat100 correlates with that of UBC4. The induction of Rat 100 may playa role in the activation of ubiquitin-dependent proteolysis during spermatogenesis.
Kummer, Anne Verfasser], and Lothar [Akademischer Betreuer] [Jänsch. "Ubiquitin and ubiquitin-like host modifications in Listeria monocytogenes infection / Anne Kummer ; Betreuer: Lothar Jänsch." Braunschweig : Technische Universität Braunschweig, 2017. http://d-nb.info/1175817945/34.
Full textMatta, Camacho Edna. "Structural studies of Ubiquitin related proteins." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110562.
Full textLes modifications post-traductionnelles des protéines par une molécule d'ubiquitine (Ub) ou par des chaînes de poly-Ub déterminent leur destin pour diverses fonctions cellulaires notamment la dégradation à travers le protéosome, l'endocytose, le tri endosomique ainsi que la réparation de l'ADN. De façon générale, trois enzymes catalysent une réaction d'ubiquitination: une enzyme d'activation (Ub-activating enzyme E1), une enzyme de conjugaison (Ub-conjugating enzyme E2), et une enzyme qui détermine la spécificité pour le substrat (specificity-determining Ub-protein ligase E3). Cette thèse porte sur trois aspects distincts impliqués dans le processus d'ubiquitination des protéines:La reconnaissance de substrats par les protéines UBR1 et UBR2: les Ub-recognins (UBR) sont des ligases E3 qui reconnaissent des résidus N-terminaux (N-degrons) comme signaux pour la dégradation des protéines. Cette reconnaissance suit une règle de rotation du nombre d'entités ciblées nommée N-end rule (règle du N-terminus). A l'aide de données de cristallographie aux rayons X, nous avons déterminé la structure du domaine UBR-box impliqué dans la reconnaissance du substrat des protéines UBR1 et UBR2 en complexe avec un N-degron. Ces structures montrent que le domaine UBR-box adopte un nouveau repliement stabilisé par trois ions zinc et qu'il forme une poche pour accueillir les N-degrons. Aussi, des mesures biochimiques d'affinité ont permis d'établir des principes moléculaires pour la reconnaissance des N-degrons qui sont chargés positivement.La fixation du substrat et son ubiquitination par la protéine UBR5: UBR5 est une Ub ligase E3 contenant un domaine catalytique HECT et un domaine de liaison peptidique, MLLE. Le domaine MLLE recrute plusieurs protéines régulatrices grâce à leur motif PAM2 composé de douze résidus. En procédant à des expériences de pull-down et à des essais d'ubiquitination, nous avons démontré que le domaine HECT interagissait avec le domaine MLLE adjacent de manière dépendante du motif PAM2. Cette interaction conduit à des changements conformationnels qui modulent le repliement et l'ubiquitination de TopBP1, un substrat d'UBR5.La reconnaissance d'Ubiquitine et de chaînes poly-Ub par le domaine UBA de la protéine Swa2: les domaines UBA (Ub-associated) sont composés d'environ quarante acides aminés présents dans des protéines associées à l'ubiquitination. Les domaines UBA se lient à des mono-Ub in vitro, mais semblent avoir une affinité supérieure pour les chaînes de poly-Ub. Un modèle structurel du domaine UBA de la protéine Swa2p en complexe avec une Ub montre que la reconnaissance de l'Ub se produit principalement par une interaction atypique grâce à l'hélice α1 du domaine UBA. Des essais de résonance plasmonique de surface combinés à de la mutagenèse ont révélé une faible affinité secondaire pour le site de liaison à l'Ub et une préférence de l'UBA de Swa2p pour la liaison aux poly-Ub. Ces résultats ont révélé un rôle potentiel du domaine UBA de Swa2p pour lier les protéines poly-ubiquitinylées in vivo.À trois niveaux différents, la reconnaissance du substrat par le règle N-fin, fixation du substrat et l'ubiquitination par une ligase E3, et la reconnaissance des espèces de l'ubiquitine par domaines UBA, cette thèse a fournir une meilleure compréhension du mécanisme qui la voie Ub emploie pour assurer la sélectivité et la processivité de garder le bon environnement homéostatique dans la cellule.
Meldrum, Jill Kathleen. "Engineering the Folding Pathway of Ubiquitin." Thesis, University of Nottingham, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.519401.
Full textMesquita, Francisco Sarmento. "Interactions between salonella and ubiquitin pathways." Thesis, Imperial College London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534978.
Full textCrespo, Solans MariÌa Dolores. "Probing the folding pathway of ubiquitin." Thesis, Nottingham Trent University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415685.
Full textSimpson, Emma Rhiannon. "Exploring the folding pathway of ubiquitin." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437025.
Full textCanning, Mary. "Ubiquitin-mediated proteolysis and Drosophila embryogenesis." Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/13305.
Full textThorne, Christopher Mark Cornelius. "Characterisation of ubiquitin specific protease 33." Thesis, University of Liverpool, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548811.
Full textGupta, Nilaksh. "UBIQUITIN-PROTEASOME SYSTEM MODULATES PLATELET FUNCTION." Cleveland State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1408896695.
Full textBingol, Baris Zinn Kai George. "Ubiquitin-proteasome system at the synapse /." Diss., Pasadena, Calif. : Caltech, 2006. http://resolver.caltech.edu/CaltechETD:etd-05272006-184911.
Full textSchubert, Alexander Fabian. "Mechanism of PINK1-mediated ubiquitin phosphorylation." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/277271.
Full textMichel, Martin Alex. "Specific recognition of atypical ubiquitin modifications." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/277694.
Full textSokratous, Kleitos. "Probing the affinity, selectivity and inhibition of ubiquitin-ubiquitin binding domain complexes by electrospray ionization mass spectrometry." Thesis, University of Nottingham, 2013. http://eprints.nottingham.ac.uk/14368/.
Full textBebington, Catherine. "Ubiquitin and ubiquitin-like proteins in the uterus and placenta of the human and non-human primate." Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312211.
Full textLionnard, Loïc. "Régulation de la stabilité de la protéine anti-apoptotique BCL2A1." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT003/document.
Full textApoptosis or programmed cell death plays a crucial role in tissue homeostasis and is regulated by the Bcl-2 proteins, which control mitochondria membrane permeability and cytochrome c release, two events that precede cell demise. Anti-apoptotic Bcl-2 family members can contribute to tumorigenesis and cause resistance to anti-cancer regimens, therefore representing important targets for novel therapeutics. BCL2A1 is an anti-apoptotic member of the BCL-2 family that contributes to chemoresistance in a subset of tumors. BCL2A1 has a short half-life due to its constitutive processing by the ubiquitin-proteasome system. This constitutes a major tumor-suppressor mechanism regulating BCL2A1 function. However, the enzymes involved in the regulation of BCL2A1 protein stability are currently unknown. Here we provide the first insight into the regulation of BCL2A1 ubiquitination. We present evidence that TRIM28 is an E3 ubiquitin-ligase for BCL2A1. Indeed, endogenous TRIM28 and BCL2A1 bind to each other at the mitochondria and TRIM28 knock-down decreases BCL2A1 ubiquitination. We also show that TRIM17 stabilizes BCL2A1 by blocking TRIM28 from binding and ubiquitinating BCL2A1, and that GSK3 is involved in the phosphorylation-mediated inhibition of BCL2A1 degradation. BCL2A1 and its close relative MCL1 are thus regulated by common factors but with opposite outcome. Finally, overexpression of TRIM28 or knock-out of TRIM17 reduced BCLA1 protein levels and restored sensitivity of melanoma cells to BRAF-targeted therapy. Therefore, our data describe a molecular rheostat in which two proteins of the TRIM family antagonistically regulate BCL2A1 stability and modulate cell death.Sommaire
Wu, George Tatung. "The role of anaphase-promoting complex in cellular differentiation and tumorigenesis /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1528351821&sid=7&Fmt=2&clientId=8424&RQT=309&VName=PQD.
Full textBINET, MARIE-NOELLE. "Structure et expression de genes d'ubiquitine de tournesol (helianthus annuus)." Strasbourg 1, 1991. http://www.theses.fr/1991STR13102.
Full textRatti, Francesca. "Role of HDAC6 in Skeletal Muscle Atrophy." Thesis, Lyon, École normale supérieure, 2014. http://www.theses.fr/2014ENSL0887.
Full textHDAC6 is a highly conserved histone deacetylase, mostly cytoplasmic. Unlike other deacetylases, HDAC6 has unique substrate specificity for non-histone proteins. Besides the deacetylation domains, HDAC6 also contains an ubiquitin-binding domain, which links HDAC6 to the ubiquitin/proteasome pathway. Skeletal muscle atrophy is a severe condition of muscle mass loss occurring during aging or in many clinical disorders as cancer, diabetes and AIDS. The maintenance of muscle mass is subtly controlled by an equilibrium between catabolic and anabolic processes. Muscle atrophy results as a partial suppression of protein synthesis and a substantial increase of protein breakdown by the ubiquitin-proteasome system, caused by the expression of a series of specific genes, the atrogenes. One of the atrogenes induced more dramatically is the muscle specific E3 ubiquitin ligase MAFbx/Atrogin-1, which takes care of the degradation of MyoD and of eIF3-f. Degradation of those two proteins inhibits expression of myotrophic genes and translation preventing the replacement of degraded proteins.We identified HDAC6 as a new atrogene. HDAC6 expression is up regulated during muscle atrophy in mouse and human through a mechanism FoxO3-dependent. In vivo depletion of this enzyme by shRNA electroporation or homologous recombination gives protection against atrophy and its inhibition during atrophy can partially reverse the muscle wasting phenotype. HDAC6 can interact with MAFbx and is required for MAFbx-mediated degradation of MyoD. According to our results, forced expression of a MyoD mutant resistant to HDAC6 and MAFbx dependent degradation prevents muscle wasting induced by denervation. Furthermore, some preliminary data show an involvement of HDAC6 in the degradation of eIF3-f and in the autophagy process in muscle tissue, revealing a double role of HDAC6 in skeletal muscle.These evidences suggest that HDAC6 potentially represents a valuable target for curative treatments
Maghames, Chantal. "Regulation of proteotoxicity through atypical NEDDylation." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT041.
Full textCells are continuously endangered by a variety of proteotoxic stresses that cause protein misfolding and accumulation. Defects in repair or elimination of protein damage can lead to the formation of toxic aggregates that have been associated with diseases, such as neurodegenerative disorders and cancer. To prevent this toxicity, cells have evolved multiple quality control processes that interact and cooperate to maintain protein homeostasis leading to cellular fitness. These processes form “the proteostasis network”, and include molecular chaperones, proteolytic machineries (lysosomes, proteasomes) and pathways for protein damage sequestration. One of the main effectors of this network is the Ubiquitin and the Ubiquitin-like molecules, such as SUMO and NEDD8. These molecules covalently modify proteins through the action of E1, E2 and E3 enzymes. Historically, it was believed that each pathway employed its own and unique set of enzymes to post-translationally modify its substrates. Ubiquitination is essential for the cellular response to stress, especially by targeting misfolded proteins for proteasomal degradation. However, we recently discovered that proteotoxic stresses including proteasome inhibition, heat shock and oxidative stress induce a global increase in protein NEDDylation. Surprisingly, this increase does not depend on the NEDD8 activating enzyme NAE, but rather on the Ubiquitin activating enzyme Ube1, and is characterized by the formation of poly-NEDD8 chains and mixed chains between NEDD8 and Ubiquitin. Importantly, this process is reversible and cell recovery is accomplished once stress is alleviated. In this study, we focused on characterizing the NEDD8 response to stress or “atypical NEDDylation” in order to understand its biological relevance under these conditions.Our results showed that atypical NEDDylation depends on Hsp70/90 and targets mainly newly synthesized damaged proteins. We showed that, after their NEDDylation/Ubiquitination, misfolded proteins are progressively translocated from the cytosol into the nucleus for proteasomal degradation. However, upon prolonged stress conditions, the activity of nuclear 26S proteasome is compromised, resulting in the accumulation of these conjugates into nuclear inclusions. These inclusions are reversible and eliminated by nuclear proteasomes once stress is alleviated. In order to identify NEDD8 targets upon these conditions, we developed a proteomic approach based on a point mutation strategy (NEDD8R74K) that enables a site-specific analysis of NEDDylated proteins. This approach in combination with SILAC allowed the identification of NEDD8, Ubiquitin, SUMO-2, and ribosomal proteins as the major NEDD8 targets upon stress. Interestingly, by SILAC proteomics we found that the main function of atypical NEDDylation is to induce the aggregation/sequestration of a specific subset of proteins within the nuclear inclusions. We showed that this NEDD8-induced aggregation protects nuclear proteasomes from a severe impairment and allows a better cell survival upon proteotoxic stress.Our study defines NEDD8 as a new effector in the proteostasis network, identifies a new cytoprotective nuclear inclusion and shows that atypical NEDDylation is essential for the cellular response to stress
Cheng, Yen-Fu. "Role of the ubiquitin-proteasome pathway in the inner ear : identification of an E3 ubiquitin ligase for Atoh1." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/96458.
Full textCataloged from PDF version of thesis.
Includes bibliographical references (pages 91-105).
Atoh1, the proneural basic-helix-loop-helix transcription factor, is critical for the differentiation of inner ear hair cells. Hair cells do not develop in mice that lack Atoh1, and overexpression of the transcription factor in embryonic ears induces differentiation of extra hair cells. The level of Atoh1 expression is under the control of a Wnt and Notch transcriptional regulatory network to keep the level of mRNA within a narrow range. Once the protein is made, it activates its own expression through an interaction with the Atoh1 enhancer, such that Atoh1 transcription is self-perpetuating. Because of this autoregulatory loop, halting transcription of the gene to maintain Atoh1 at an appropriate level would require that the amount of protein be decreased. Since the ubiquitin-proteasome pathway regulates catabolism of key regulatory proteins, we assessed its role in the degradation of Atoh1. E3 ubiquitin ligases confer substrate specificity to degradation of proteins by transferring a ubiquitin tag to a specific protein substrate. Using an immunoprecipitation/mass spectrometry screening approach, we identified Huwe1, a HECT domain E3 ubiquitin ligase, as an Atoh1 binding partner. We validated the binding between Atoh1 and Huwe1 through reciprocal co-immunoprecipitation and mass spectrometry. We found that Huwe1 promoted polyubiquitylation of Atoh1 through a lysine 48-linked polyubiquitin chain. Mutation at a catalytic cysteine within the HECT domain of Huwe1 reduced the polyubiquitylation. We also defined a motif in the C-terminus of Atoh1 responsible for interaction with Huwe1. Inhibition of proteasomal activity, as well as Huwe1 depletion, stabilized Atoh1 in the cochlea and resulted in generation of new hair cells in the newborn cochlea.
by Yen-Fu Cheng.
Ph. D.
Crimmins, Stephen Lewis. "Characterization and functional analysis of Usp14." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2007p/crimmins.pdf.
Full textParvatiyar, Kislay. "Ubiquitin Dependent Regulation of Innate Antiviral Signaling." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/651.
Full textDixon, James Edward. "Arkadia Family Ubiquitin-Ligases in TGFp Signalling." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486282.
Full textPtak, Christopher. "Ubiquitin conjugating enzymes, relating form to function." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq23058.pdf.
Full textMenéndez, Benito Victoria. "The ubiquitin-proteasome system during proteotoxic stress /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-706-5/.
Full textAdlington, Jennifer. "Ubiquitin binding by the p62 UBA domain." Thesis, University of Nottingham, 2013. http://eprints.nottingham.ac.uk/14519/.
Full textTinsley, Caroline L. "Multi-protein complexes, ubiquitin and muscle disease." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510248.
Full textGhannam, Khetam [Verfasser]. "Ubiquitin proteasome system and myopathies / Khetam Ghannam." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1075493374/34.
Full textMarsh, Sadie. "Ubiquitin-like proteins in the human uterus." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272574.
Full textMin, Mingwei. "Decoding the mitotic exit ubiquitin-proteasome system." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708388.
Full textNathan, James Alexander. "The RING-CH ubiquitin E3 ligase MARCH7." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612286.
Full text