Role of the ubiquitin-like modifier FAT10 in protein degradation and ...

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Introduction Protein Degradation Nearly all proteins in our body are not stable constituents but are rather sub- ject to dynamic turnover through degradation and neosynthesis. Protein degradation is a highly complex and tightly regulated process and is essential for a broad range of cellular functions. These include processes spanning from the response to nutrient starvation over quality control to activation and silencing of transcription, regulation of the cell cycle, signal transduction, apoptosis and antigen presentation. Cellular proteolysis in eukaryotic cells is mediated by two distinct systems, the proteasome and the lysosome. The proteasome is a large, barrel-shaped protease which is responsible for the degradation of about 80% of all intracellular proteins, the majority of which are short-lived. Access to the proteolytic core of the proteasome is regulated by covalent modification of the targeted proteins with a ubiquitin “tag”. The lysosome, in contrast, is a membrane- enclosed organelle which contains various proteolytic enzymes with a functional optimum at an acidic pH. Exogenous proteins can be targeted to the lysosome either by receptor-mediated endocytosis or by pino- or phagocytosis, which can be summarized as heterophagy. In addition, the lysosome is also involved in the bulk degradation of cellular proteins as well as the degradation of organelles in a process termed autophagy. 9
The Ubiquitin-Proteasome-System The Proteasome The 20S Proteasome Introduction The proteasome, a large, cylindrical multi-enzyme complex, is the central ele- ment of the ubiquitin-proteasome system (UPS). It can be subdivided into two dissociable assemblies; the core complex, also known as the 20S proteasome, and one or two regulatory particles which cap the ends of the core particle. Four hetero-heptameric rings are axially stacked to form the 20S proteasome, where subunits α1-α7 make up the outer and subunits β1-β7 the inner two rings (Fig. 1). Enzymatic activity is restricted to the central lumen of the cylinder, which effec- tively prevents unspecific access to the active sites and thus aberrant degradation. Through N-terminal extensions, the α-subunits further occlude the central pore, which can only be opened by association with a regulatory complex (Groll et al., 2000). Only three of the β-subunits in each ring (β1, β2 and β5) display catalytic activity, and their active sites point toward the inside of the proteolytic chamber. All of these subunits are threonine-proteases, but each of them displays different proteolytic preferences, which have been classified ac- cording to the residue N-terminal of the cleaved peptide-bond: acidic (caspase- like, β1), basic (trypsin-like, β2), and hydrophobic (chymotrypsin-like, β5) (Groll and Clausen, 2003). The cylindrical shape of the 20S proteasome promotes a pro- cessive degradation of its substrates by preventing the dissociation of partially processed polypeptides, and thus releases short peptides ranging from three to 25 residues. These peptides can now be further processed into single amino acids by cytoplasmatic aminopeptidases, or they can be – if they meet the requirements – loaded onto MHC class I molecules and subsequently be presented to circulating lymphocytes (Coux et al., 1996; Baumeister et al., 1998). In higher vertebrates, the release of interferon (IFN)-γ leads to the induction of three additional, non-essential subunits: β1i (LMP2), β2i (MECL-1) and β5i (LMP7), which are incorporated into the proteasome during neosynthesis. Pro- teasomes which contain these inducible subunits are termed “immunoprotea- somes” and display an altered cleavage pattern which could be shown to gen- erate more peptides suitable for presentation (Groettrup et al., 2001a,b; Goldberg et al., 2002). In addition to these three inducible subunits, one other differentially 10
Page 1 and 2: Role of the ubiquitin-like modifier
Page 3 and 4: Acknowledgements . . . . . . . . .
Page 5 and 6: Summary / Zusammenfassung English F
Page 7 and 8: Summary In conclusion, these result
Page 9: Summary nicht von der katalytischen
Page 13 and 14: Introduction Figure 1: The 26S prot
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Page 17 and 18: Introduction majority of ubiquitin-
Page 19 and 20: Introduction example contained in t
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Page 23 and 24: Introduction Figure 4: Comparison o
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Page 27 and 28: Introduction Interestingly, a recen
Page 29 and 30: The Autophagy-Lysosome System Intro
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Page 33 and 34: Introduction The transport of misfo
Page 35 and 36: Introduction where the proteasome i
Page 37 and 38: Chapter 1 The UBA domains of NUB1L
Page 39 and 40: Introduction Chapter 1 Ubiquitin, a
Page 41 and 42: Chapter 1 no correlation between th
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Page 45 and 46: Chapter 1 Figure 8: Accelerated deg
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Page 49 and 50: Chapter 1 ing SUMO-1-GFP or the C-t
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Page 53 and 54: Chapter 1 Figure 13: Co-immunopreci
Page 55 and 56: Chapter 1 domains of NUB1L is requi
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Chapter 2 Degradation of FAT10 by t
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Introduction Chapter 2 The proteaso
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Chapter 2 From our previous data it
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Chapter 2 Figure 14: Purified compo
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Chapter 2 evaluation of the NUB1L b
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Chapter 2 teins which contain intri
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Chapter 2 Combined with our studies
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Chapter 2 Recombinant expression of
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Chapter 2 et al., 2003), both at a
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Abstract Chapter 3 During misfolded
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Chapter 3 tion between the UPS and
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Chapter 3 Figure 18: HDAC6 interact
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Chapter 3 Figure 19: Both the BUZ d
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Chapter 3 of HDAC6 was required for
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Chapter 3 precipitates with HDAC6 (
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90 Chapter 3
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Chapter 3 Figure 23: The model conj
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Chapter 3 HDAC6 is required for the
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Chapter 3 Figure 26: Both ubiquitin
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Chapter 3 also revealed endogenous,
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Chapter 3 and/or its conjugates is
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Chapter 3 (Hipp et al., 2005), pEGF
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Chapter 4 FAT10-deficient mice disp
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Chapter 4 Once the infection is cle
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Chapter 4 As both wild-type as well
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Chapter 4 Peptides. The synthetic p
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Introduction Chapter 5 Antibodies a
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Chapter 5 binant human and mouse GS
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Chapter 5 Figure 34: The antibodies
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Chapter 5 Figure 36: The antibody s
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Discussion 30 years ago, ubiquitin
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Discussion monomeric ubiquitin as w
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Discussion Alternatively, FAT10 cou
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References D. T. Akey, X. Zhu, M. D
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References Y.-H. Chiu, Q. Sun, and
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References S. Gunawardena, L.-S. He
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References J. A. Johnston, M. E. Il
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References F. Lévy, N. Johnsson, T
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References J.-H. Park, H.-S. Jong,
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References P. Schreiner, X. Chen, K
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References S. Vijay-Kumar, C. E. Bu
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Abbreviations aa amino acid AAA ATP
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Amino Acids Alanine Ala A Arginine
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