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

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Introduction The ATG12-ATG5 complex then associates with ATG16 and is thought to create a scaffold for the formation of the isolation membrane (Xie and Klionsky, 2007). As autophagy functions by engulfing a portion of the cytoplasm, it was generally thought to be a non-selective degradation system. However, this view has recently been challenged by a number of reports which describe the specific targeting of certain substrates to the autophagosome. Misfolded Protein Stress, Aggresomes and the Connection between Autophagy and the UPS The existence of misfolded proteins in cells is an inevitable consequence of par- tial unfolding during thermal or oxidative stress and of alterations in primary structure caused by mutation, translational misincorporation or premature ter- mination. Due to the exposure of hydrophobic regions, misfolded proteins are prone to aggregation, and – if not immediately cleared – ultimately accumulate in insoluble cytoplasmatic or nuclear inclusions (Kopito, 2000). The accumulation of protein aggregates has been tightly linked to neuronal degeneration or organ failure in a number of diseases such as Alzheimer’s, Parkinson’s or Huntington’s disease and alcohol or drug induced liver damage (Gregersen et al., 2006). Al- though the exact reasons behind the cytotoxicity of protein aggregates remain unknown, a number of likely mechanisms have been proposed: First of all, the accumulation of aggregates refractory to unfolding could lead to impairment of the ubiquitin-proteasome system simply by “clogging” the proteasome, as the unfolding of its substrates is a prerequisite for their degradation (Bence et al., 2001; Bennett et al., 2005). Alternatively, aggregates could lead to the disruption of microtubule-dependent axonal transport (Gunawardena et al., 2003), or they could directly interact with transcription factors or membrane receptors, which might result in an aberrant activation of signal transduction pathways (Yan et al., 2000). In any case, whatever the reason for the cytotoxicity of misfolded proteins, cells have evolved a number of ways to counter the formation of protein aggregates. First in line are the molecular chaperones, which transiently associate with un- folded or partially folded intermediates and shelter hydrophobic surfaces from forming inappropriate intra- or intermolecular contacts. Chaperones are con- stitutively active in the quality control of nascent polypepdides, but can also be 29
Introduction Figure 5: Molecular machinery of autophagy. Two ubiquitin-like systems are required for formation of the isolation membrane and couple ATG8 (LC3) and ATG12 to phosphatidylethanolamine (PE) and ATG5, respectively. The five C-terminal amino acids of ATG8 are cleaved of by ATG4 to reveal glycine 120 (G120), which is required to link the protein after activation by ATG7 and ligation by ATG3 to PE in the autophagosomal membrane (green circles). Similarly, glycine 140 (G140) is used by ATG7 and ATG10 to couple ATG12 to ATG5. This complex then localizes to the outer membrane of the forming autophagosome (blue squares). Upon autophagosome completion, the ATG12-ATG5 complex recycles from the outer membrane, and only ATG8 remains associated with the completed autophagosome. Autophagosomes then fuse with late endosomes and lysosomes for degradation of their cargo and their intravesicular membranes. (Modified from Schmid and Münz, 2007). 30
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 and 10: Summary nicht von der katalytischen
Page 11 and 12: The Ubiquitin-Proteasome-System The
Page 13 and 14: Introduction Figure 1: The 26S prot
Page 15 and 16: Introduction are the major source o
Page 17 and 18: Introduction majority of ubiquitin-
Page 19 and 20: Introduction example contained in t
Page 21 and 22: Introduction two modifiers apart fr
Page 23 and 24: Introduction Figure 4: Comparison o
Page 25 and 26: Introduction dependent apoptosis in
Page 27 and 28: Introduction Interestingly, a recen
Page 29: The Autophagy-Lysosome System Intro
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
Page 43 and 44: Chapter 1 covered proteins were sep
Page 45 and 46: Chapter 1 Figure 8: Accelerated deg
Page 47 and 48: Chapter 1 Treatment with IFN-γ and
Page 49 and 50: Chapter 1 ing SUMO-1-GFP or the C-t
Page 51 and 52: Chapter 1 Figure 12: Accelerated de
Page 53 and 54: Chapter 1 Figure 13: Co-immunopreci
Page 55 and 56: Chapter 1 domains of NUB1L is requi
Page 57 and 58: Chapter 1 Rad23 (Verma et al., 2004
Page 59 and 60: Chapter 1 FAT10-GFP expressing vect
Page 61 and 62: Chapter 2 Degradation of FAT10 by t
Page 63 and 64: Introduction Chapter 2 The proteaso
Page 65 and 66: Chapter 2 From our previous data it
Page 67 and 68: Chapter 2 Figure 14: Purified compo
Page 69 and 70: Chapter 2 evaluation of the NUB1L b
Page 71 and 72: Chapter 2 teins which contain intri
Page 73 and 74: Chapter 2 Combined with our studies
Page 75 and 76: Chapter 2 Recombinant expression of
Page 77 and 78: Chapter 2 et al., 2003), both at a
Page 79 and 80: 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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