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

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Introduction bodies, Mallory-Denk bodies, the neurofibrillary tangles of Alzheimer’s disease and huntingtin aggregates (Zatloukal et al., 2002; Kuusisto et al., 2001; Nagaoka et al., 2004), although the domain responsible for mediating its localization to aggresomes has yet to be identified. Thus, p62 appears to function as a shuttling factor which can alternate between the delivery of polyubiquitylated proteins to either the proteasome or the aggresome or even directly into the autophagosomal vesicle. Indeed, p62 could be shown to target tau for proteasomal degradation (Babu et al., 2005), while it was also able to direct mutated huntingtin to the autophagosome (Bjørkøy et al., 2005). HDAC6 HDAC6 (histone deacetylase 6) is a cytoplasmatic class II deacetylase (Verdel and Khochbin, 1999; Yang and Grégoire, 2005) and is responsible for the deactylation of α-tubulin (Hubbert et al., 2002; Matsuyama et al., 2002; Zhang et al., 2003b), HSP90 (Bali et al., 2005) and cortactin (Zhang et al., 2007), although it could be shown to also deacetylate histones in vitro (Haggarty et al., 2003). HDAC6 is the only member of the histone deacetylase family which encompasses two catalytic domains and presumably does not rely on dimerization to exert its catalytic function (Zhang et al., 2006b). In addition to its two catalytic domains, HDAC6 possesses a SE14 repeat domain, which acts as a cytoplasmatic retention signal (Bertos et al., 2004), a dynein binding domain (Kawaguchi et al., 2003) and a C- terminal BUZ domain, which is able to interact with polyubiquitin chains as well as monomeric ubiquitin (Seigneurin-Berny et al., 2001; Hook et al., 2002). Under conditions of misfolded protein stress HDAC6 is able to associate simul- taneously with the dynein motor complex through its dynein binding domain as well as with polyubiquitylated proteins through its BUZ domain. Through these interactions, it is able mediate the relocalization of polyubiquitylated cargo to the aggresome via retrograde transport along the microtubule network (Kawaguchi et al., 2003). HDAC6 associates with the chaperone-like AAA ATPase p97/Cdc48 (Seigneurin-Berny et al., 2001), which is also able to associate with the proteasome and assists in the degradation of misfolded proteins (Römisch, 2006; Rumpf and Jentsch, 2006). p97/Cdc48 is able to control the fate of misfolded polyubiquitylated proteins by dissociating them from HDAC6 and redirecting them to proteasomal degradation (Boyault et al., 2006). Furthermore, HDAC6 is responsible for transporting proteins modfied with K63-linked polyubiquitin chains directly to the aggresome and for subsequent autophagic degradation even under conditions 33
Introduction where the proteasome is functioning normally (Olzmann et al., 2007; Olzmann and Chin, 2008). Moreover, HDAC6 has been found to be a component of Lewy bodies as well as of aggresomes induced by proteasome inhibition or ER stress (Kawaguchi et al., 2003), is required for the clearance of mutated huntingtin via autophagy (Iwata et al., 2005) and could be shown to mediate the rescue of neurodegeneration by compensatory autophagy (Pandey et al., 2007b,a). In addition to its role in the transport of polyubiquitylated proteins to the aggresome, HDAC6 is also involved in its autophagic clearance by transporting autophagosomal membranes as well as lysosomes to the pericentriolar region, although the domain which is responsible for the binding of these structures remains uniden- tified (Iwata et al., 2005). Interestingly, although catalytic activity of HDAC6 is neither required for the assiociation with dynein nor for the binding of polyubiquitylated cargo, most studies reveal the actual transport of cargo to be dependent on its enzymatic function. Although the reasons for this requirement are un- known, this effect could be attributed to the modulation of tubulin stability or kinesin-1 association through its acetylation status (Palazzo et al., 2003; Reed et al., 2006). In addition to its role in the transport of polyubiquitylated proteins, HDAC6 is also involved in controlling the cellular response to protein aggregates. A re- cent report has demonstrated HDAC6 to act as a sensor for the accumulation of polyubiquitylated proteins and to mediate the induction of major cellular chap- erones by triggering the release of heat-shock factor 1 (HSF1) from a repressive HDAC6/HSF1/HSP90 complex (Boyault et al., 2007). Interestingly, this function of HDAC6 is independent of its catalytic activity, although HSP90 has been identified as a substrate of HDAC6-mediated deacetylation. Furthermore, HDAC6 has been found to be a critical component of stress granules, which are dynamic cytoplasmatic structures involved in reversible translational repression as a response to environmental stress (Kwon et al., 2007). Through deactylation of HSP90, HDAC6 is able to modulate its chaperone activity (Bali et al., 2005) and ultimately control activation of the glucocorticoid re- ceptor (Kovacs et al., 2005; Murphy et al., 2005) and growth factor-induced actin remodeling as well as endocytosis (Gao et al., 2007). Probably through a com- bination of HSP90 mediated actin remodeling and deacetylation of cortactin as well as α-tubulin, HDAC6 is involved in the control of cell motility (Tran et al., 2007; Zhang et al., 2007), lymphocyte chemotaxis (Cabrero et al., 2006) and for- mation of the immune synapse (Serrador et al., 2004), although it might further contribute to these processes via deacetylase-independent scaffolding functions 34
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 and 30: The Autophagy-Lysosome System Intro
Page 31 and 32: Introduction Figure 5: Molecular ma
Page 33: Introduction The transport of misfo
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
Page 81 and 82: Chapter 3 tion between the UPS and
Page 83 and 84: Chapter 3 Figure 18: HDAC6 interact
Page 85 and 86:
Chapter 3 Figure 19: Both the BUZ d
Page 87 and 88:
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
Page 95 and 96:
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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