4.6 Immuno- and constitutive proteasome degradation
4.6.2 Mechanistic aspects of the immunoproteasome function
Some of the findings published by Seifert et al. were not fully reproducible (Figure 37) (Figure 38) (Nathan et al., 2013b). The proposed altered function of IPs in proteostasis during an ongoing immune response compared to SPs remains therefore questionable. Most strikingly, it remains an open question how, mechanistically, changes inside the CP due to the incorporation of LMP7, LMP2 and MECL-1 could influence the degradation process, including substrate recognition and processing. The binding of substrates is mainly mediated by the RP subunits Rpn10 and Rpn13, which are the same in 26S SPs and IPs (Husnjak et al., 2008; Saeki et al., 2002). In addition, the gating mechanism for processing and translocation of the unfolded substrate into the CP, which is regulated by the PA, was suggested to be similar for IPs and SPs, based on recent structural analysis (Huber et al., 2012). Huber et al., however, also suggested that peptide bond hydrolysis might be favored by an increased hydrophilicity of the active site of LMP7 in the IP. Altered peptide hydrolysis for the different subunits are well known, but it remains doubtful whether this leads to a decrease or increase in total proteasome capacity. Especially, since other peptidase activities are reduced, as it is known for the caspase-like activity of β1 due to the replacement by MECL-1 (Rock and Goldberg, 1999). It is well accepted, that IPs generate immunodominant peptides with higher efficiency and faster kinetics during infection (Deol et al., 2007). But these findings can be
likewise explained by the well-known alterations in the quality of peptidase activity between SPs and IPs. An overall enhancement of the degradation capacity does not contribute to a better understanding of the known role of IPs in MHC-I peptide generation.
Currently, IP inhibitors are tested in preclinical studies in the treatment of rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and cancer undermining the beneficial effect of IP inhibition (Basler et al., 2010; Basler et al., 2014; Muchamuel et al., 2009; Singh et al., 2011). On the other hand the identification of point mutations in IP subunits that are associated with specific diseases provides direct evidence that a loss in IP function can lead to severe sickness. Knowledge about the actual impact of these mutations, not only on the catalytic activity itself but also on structural changes in the CP, is of special need. Being aware of the heterogeneity of proteasome subtypes, their immunologic and non-immunologic functional differences and diverse expression profiles, further insight into functional relevance of this heterogeneous proteolytic complex will be necessary.
129
Tables and figures
Table 1: characterized ULMs (van der Veen and Ploegh, 2012) ... 7 Table 2: siRNA for knock down experiments ... 42 Table 3: primer for quantitative RT-PCR ... 43 Table 4: LightCycler program for huFAT10 and GAPDH ... 43 Table 5: LightCycler program for mHPRT ... 43 Table 6: LightCycler program for mFAT10 ... 44 Table 7: plasmids ... 44 Table 8: QuikChange Lightning Multi Site-Directed Mutagenesis Kit (Stratagene, Amsterdam,
The Netherlands) ... 46 Table 9: QuikChange II XL Site-Directed Mutagenesis Kit (Stratagene, Amsterdam, The
Netherlands)... 46 Table 10: primer for genotyping ... 49 Table 11: FAT10 genotyping ... 50 Table 12: NRAMP1 genotyping... 50 Table 13: antibodies used for immunoblot ... 55 Table 14: antibodies used for immunohistochemistry ... 56 Table 15: antibodies used for flow cytometry ... 57
Figure 1: Ubiquitin conjugate formation and ubiquitin linkage types. 6 Figure 2: Ribbon diagram of the resolved ubiquitin and predicted FAT10 structure. 9
Figure 3: The eukaryotic 26S proteasome holoenzyme. 16
Figure 4: Orchestration of autophagy. 23
Figure 5: Regulation of autophagy induction. 25
Figure 6: Domain structure of autophagy receptors. 27
Figure 7: Model of S. Typhimurium infection. 33
Figure 8: The multiple roles of HDAC6 in proteostasis. 38
Figure 9: Endogenous p62 co-localizes with endogenous FAT10. 60
Figure 10: Monitoring autophagosomal flux. 61
Figure 11: Expression of mCherry-EGFP tagged FAT10, ubiquitin and p62. 62 Figure 12: The mCherry-EGFP tag allows tracking of FAT10 into acidified compartments. 63 Figure 13: mCherry-EGFP-FAT10 is not specifically targeted to autolysosomes. 65 Figure 14: FAT10 is not degraded via the lysosomal degradation pathway 67 Figure 15: pIRES-mCherry-EGFP-62-FAT10 expression in HeLa cells. 68 Figure 16: FAT10 does not influence lysosomal targeting of tf-p62. 69
Figure 17: Model of the conditional GFP expressing S. Typhimurium strain SHF2. 70 Figure 18: Characterization of SHF2 during early infection. 71 Figure 19: FAT10 decorates autophagy targeted S. Typhimurium. 71
Figure 20: FAT10 does not decorate L. monocytogenes. 74
Figure 21: Fluorescent FAT10 signals correlate with p62-positive but less with NDP52-positive
microdomains. 76
Figure 22: FAT10 is not covalently conjugated to S. Typhimurium in vitro. 78 Figure 23: FAT10 decoration of SHF2 in dependence of UBA6 and USE1 expression. 79
Figure 24: Exogenous FAT10 expression in HUVECs. 80
Figure 25: FAT10 decoration of S. Typhimurium and xenophagy follow the same kinetic. 81 Figure 26: Monomeric FAT10 levels decrease during infection with S. Typhimurium. 82 Figure 27: FAT10 deficiency in HUVECs does not change bacterial replication in vitro. 84 Figure 28: FAT10 deficiency in MEFs does not change bacterial replication in vitro. 85 Figure 29: FAT10 deficiency in macrophages does not change bacterial replication in vitro. 86 Figure 30: FAT10 overexpression does not significantly change bacterial replication in vitro. 87 Figure 31: NRAMP1 transgenic FAT10 knockout mice show a higher bacterial load in
mesenteric lymph nodes. 88
Figure 32: Survival curve of NRAMP1 transgenic wild type and FAT10 knockout mice after
orally inoculated S. Typhimurium. 89
Figure 33: NRAMP1 transgenic FAT10 knockout mice are more sensitive to orally inoculated
S. Typhimurium. 90
Figure 34: Schematic illustration of the 35S-cystein labelling. 92 Figure 35: FAT10 is not preferentially conjugated to newly translated proteins. 93 Figure 36: Ubiquitin is not preferentially conjugated to newly translated proteins. 95 Figure 37: The amount of high molecular weight polyubiquitin conjugates does not change in
response to IFN-γ. 97
Figure 38: The number of ALIS per cell increased to the same extent in LMP7-deficient and wild
type MEFs. 99
131
Abbreviations
3-MA 3-Methyladenine AA amino acid
AIPL1 aryl hydrocarbon receptor-Interacting Protein-Like 1 AP-1 activator protein 1
ARE antioxidant response element Atg8 autophagy related gene ATP adenosine triphosphate
CANDLE chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature CMA chaperone-mediated autophagy
CP core particle
Cvt cytoplasm-to-vacuole targeting DAG diacylglycerol
DC dendritic cell
DSS dextran sodium sulfate DUB de-ubiquitinating enzyme EAE autoimmune encephalomyelitis
ESCRT endosomal sorting complexes required for transport FAE follicle associated epithelia
FAT10 HLA-F locus associated transcript 10 FOXP3 forkhead box protein P3
GWAS genome-wide association study HDAC histone de-acetylase
HECT homologous to E6-AP carboxyl terminus HUB-1 homology to UB-1
IBR in between RING IP immune precipitation IRF interferon regulatory factor ISG15 interferon stimulated gene 15 IκBα inhibitor of kappaB α
kDa kilo Dalton KO knockout
LAP LC3 associated phagocytosis LC3 light chain 3
LCA Leber’s congenital amaurosis LIR LC3 interacting region LMP low molecular mass protein LPS lipopolysaccharide
LRRFIP2 leucine-rich repeat fli-I-interacting protein 2 LULL1 lumenal domain-like LAP1
MAD2 mitotic arrest deficient 2-like protein 1
MECL-1 multicatalytic endopeptidase complex subunit-1 MNSFβ monoclonal nonspecific suppressor factor β MTOC microtubule organizing center
mTORC mammalian target of rapamycin complex MUB membrane anchored UBL-fold
MVB multivesicular body MZF-1 myeloid zinc finger 1 NDP52 nuclear dot protein 52
NEDD8 neural precursor cell-expressed, developmentally downregulated 8 NEM N-ethylmaleimide
NEMO NF-κB essential modulator NeoR neomycin resistance NF-κB nuclear factor kappa b
NRAMP1 natural resistance-associated macrophage protein 1 PA proteasome activator
PAMP pathogen associated molecular pattern PAS phagosome assembly site
PE phosphatidylethanolamine PI3P phosphatidylinositol-3-phosphate PIK PI3 kinase
PKR double-stranded RNA-dependent protein kinase R pMΦ peritoneal macrophage
PRR pattern recognition receptor PtdSer phosphatidyl serine
PTEN phosphatase and tensin homologue PTM post translational modifications
RANKL receptor activator of nuclear factor kappa-B ligand RBR RING-between-RING
RING really interesting gene RP regulatory particle
RTECs renal tubular epithelial cells
SAE SUMO-activating enzyme SG stress granules
SIM SUMO interacting motive
Slc11a1 solute carrier family 11 member 1 SNP single nucleotide polymorphism SP standard proteasomes
SPI Salmonella pathogenicity island
STAT signal transducers and activators of transcription SUMO small ubiquitin like modifiers
T3SS type III secretion system TLR toll like receptor
TRAF tumor necrosis factor receptor-associate factor UBA ubiquitin activating enzyme
UBC ubiquitin conjugating enzyme UBL ubiquitin like proteins
UDP ubiquitin domain proteins UFM-1 ubiquitin-fold modifier-1 UIM ubiquitin interacting motive ULK uncoordinated-1-like kinase ULM ubiquitin like modifier URM-1 ubiquitin-related modifier 1 USE1 UBA6-specific E2-enzyme
USP ubiquitin-specific-processing protease VCP valosin-containing protein
VPS vacuolar protein sorting-associated protein WT wild type
Amino acid Three letter code One letter code
Alanine Ala A
Arginine Arg R
Asparagine Asn N
Aspartic acid Asp D
Cysteine Cys C
Glutamic acid Glu E
Glutamine Gln Q
Glycine Gly G
Histidine His H
Isoleucine Ile I
Leucine Leu L
Lysine Lys K
Methionine Met M
Phenylalanine Phe F
Proline Pro P
Serine Ser S
Threonine Thr T
Tryptophan Trp W
Tyrosine Tyr Y
Valine Val V
135
References
Agarwal, A. K., Xing, C., DeMartino, G. N., Mizrachi, D., Hernandez, M. D., Sousa, A. B., Martínez de Villarreal, L., dos Santos, H. G. and Garg, A. (2010). PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am. J. Hum. Genet. 87, 866–72.
Aichem, A., Pelzer, C., Lukasiak, S., Kalveram, B., Sheppard, P. W., Rani, N., Schmidtke, G. and Groettrup, M. (2010). USE1 is a bispecific conjugating enzyme for ubiquitin and FAT10, which FAT10ylates itself in cis. Nat. Commun. 1, 13.
Aichem, A., Kalveram, B., Spinnenhirn, V., Kluge, K., Catone, N., Johansen, T. and Groettrup, M. (2012).
The proteomic analysis of endogenous FAT10 substrates identifies p62/SQSTM1 as a substrate of FAT10ylation. J. Cell Sci. 125, 4576–85.
Aichem, A., Catone, N. and Groettrup, M. (2014). Investigations into the auto-FAT10ylation of the bispecific E2 conjugating enzyme USE1. FEBS J. 281, 1848–1859.
Akey, D. T., Zhu, X., Dyer, M., Li, A., Sorensen, A., Blackshaw, S., Fukuda-Kamitani, T., Daiger, S. P., Craft, C. M., Kamitani, T., et al. (2002). The inherited blindness associated protein AIPL1 interacts with the cell cycle regulator protein NUB1. Hum. Mol. Genet. 11, 2723–33.
Aly, T. A., Baschal, E. E., Jahromi, M. M., Fernando, M. S., Babu, S. R., Fingerlin, T. E., Kretowski, A., Erlich, H. A., Fain, P. R., Rewers, M. J., et al. (2008). Analysis of Single Nucleotide Polymorphisms Identifies Major Type 1A Diabetes Locus Telomeric of the Major histocompatibility complex. Diabetes 57, 770–6.
Amerik, A. Y. and Hochstrasser, M. (2004). Mechanism and function of deubiquitinating enzymes. Biochim.
Biophys. Acta 1695, 189–207.
Aravind, L. and Koonin, E. V (2000). The U box is a modified RING finger - a common domain in ubiquitination. Curr. Biol. 10, R132–4.
Arima, K., Kinoshita, A., Mishima, H., Kanazawa, N., Kaneko, T., Mizushima, T., Ichinose, K., Nakamura, H., Tsujino, A., Kawakami, A., et al. (2011). Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc. Natl. Acad. Sci. U. S. A. 108, 14914–9.
Arpaia, N., Godec, J., Lau, L., Sivick, K. E., McLaughlin, L. M., Jones, M. B., Dracheva, T., Peterson, S.
N., Monack, D. M. and Barton, G. M. (2011). TLR signaling is required for Salmonella typhimurium virulence. Cell 144, 675–88.
Babu, J. R., Geetha, T. and Wooten, M. W. (2005). Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J. Neurochem. 94, 192–203.
Baker, T. A. and Sauer, R. T. (2006). ATP-dependent proteases of bacteria: recognition logic and operating principles. Trends Biochem. Sci. 31, 647–53.
Barton, C. H., Whitehead, S. H. and Blackwell, J. M. (1995). Nramp transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways. Mol. Med. 1, 267–279.
Basler, M., Moebius, J., Elenich, L., Groettrup, M. and Monaco, J. J. (2006). An altered T cell repertoire in
136
MECL-1-deficient mice. J. Immunol. 176, 6665–72.
Basler, M., Dajee, M., Moll, C., Groettrup, M. and Kirk, C. J. (2010). Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J. Immunol. 185, 634–41.
Basler, M., Lauer, C., Moebius, J., Weber, R., Przybylski, M., Kisselev, A. F., Tsu, C. and Groettrup, M.
(2012). Why the structure but not the activity of the immunoproteasome subunit low molecular mass polypeptide 2 rescues antigen presentation. J. Immunol. 189, 1868–77.
Basler, M., Kirk, C. J. and Groettrup, M. (2013). The immunoproteasome in antigen processing and other immunological functions. Curr. Opin. Immunol. 25, 74–80.
Basler, M., Mundt, S., Muchamuel, T., Moll, C., Jiang, J., Groettrup, M. and Kirk, C. J. (2014). Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis. EMBO Mol. Med. 6, 226–38.
Bates, E. E., Ravel, O., Dieu, M. C., Ho, S., Guret, C., Bridon, J. M., Ait-Yahia, S., Brière, F., Caux, C., Banchereau, J., et al. (1997). Identification and analysis of a novel member of the ubiquitin family expressed in dendritic cells and mature B cells. Eur. J. Immunol. 27, 2471–7.
Baugh, J. M., Viktorova, E. G. and Pilipenko, E. V (2009). Proteasomes can degrade a significant proportion of cellular proteins independent of ubiquitination. J. Mol. Biol. 386, 814–27.
Becker, J., Barysch, S. V, Karaca, S., Dittner, C., Hsiao, H.-H., Berriel Diaz, M., Herzig, S., Urlaub, H.
and Melchior, F. (2013). Detecting endogenous SUMO targets in mammalian cells and tissues. Nat.
Struct. Mol. Biol. 20, 525–31.
Benjamin, J. L., Sumpter, R., Levine, B. and Hooper, L. V (2013). Intestinal epithelial autophagy is essential for host defense against invasive bacteria. Cell Host Microbe 13, 723–34.
Bett, J. S., Kanuga, N., Richet, E., Schmidtke, G., Groettrup, M., Cheetham, M. E. and van der Spuy, J.
(2012). The inherited blindness protein AIPL1 regulates the ubiquitin-like FAT10 pathway. PLoS One 7, e30866.
Beuzón, C. R., Méresse, S., Unsworth, K. E., Ruíz-Albert, J., Garvis, S., Waterman, S. R., Ryder, T. A., Boucrot, E. and Holden, D. W. (2000). Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. EMBO J. 19, 3235–49.
Bhan, M. K., Bahl, R. and Bhatnagar, S. (2005). Typhoid and paratyphoid fever. Lancet 366, 749–62.
Bianchi, K. and Meier, P. (2009). A tangled web of ubiquitin chains: breaking news in TNF-R1 signaling. Mol.
Cell 36, 736–42.
Birmingham, C. L., Smith, A. C., Bakowski, M. a, Yoshimori, T. and Brumell, J. H. (2006). Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J. Biol. Chem.
281, 11374–83.
Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., Stenmark, H. and Johansen, T. (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–14.
Bjørkøy, G., Lamark, T., Pankiv, S., Øvervatn, A., Brech, A. and Johansen, T. (2009). Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 452, 181–97.
Blackwell, J. M. (2001). Genetics and genomics in infectious disease susceptibility. Trends Mol. Med. 7, 521–6.
137
Bodemann, B. O., Orvedahl, A., Cheng, T., Ram, R. R., Ou, Y.-H., Formstecher, E., Maiti, M., Hazelett, C.
C., Wauson, E. M., Balakireva, M., et al. (2011). RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144, 253–67.
Botteaux, A., Hoste, C., Dumont, J. E., Van Sande, J. and Allaoui, A. (2009). Potential role of Noxes in the protection of mucosae: H(2)O(2) as a bacterial repellent. Microbes Infect. 11, 537–44.
Boyle, K. B. and Randow, F. (2013). The role of “eat-me” signals and autophagy cargo receptors in innate immunity. Curr. Opin. Microbiol. 16, 339–48.
Bradley, D. J. and Kirkley, J. (1977). Regulation of Leishmania populations within the host. I. the variable course of Leishmania donovani infections in mice. Clin. Exp. Immunol. 30, 119–29.
Brown, M. G., Driscoll, J. and Monaco, J. J. (1991). Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes. Nature 353, 355–7.
Brown, D. E., Libby, S. J., Moreland, S. M., McCoy, M. W., Brabb, T., Stepanek, A., Fang, F. C. and Detweiler, C. S. (2013). Salmonella enterica causes more severe inflammatory disease in C57/BL6 Nramp1G169 mice than Sv129S6 mice. Vet. Pathol. 50, 867–76.
Brumell, J. H., Steele-Mortimer, O. and Finlay, B. B. (1999). Bacterial invasion: Force feeding by Salmonella. Curr. Biol. 9, R277–R280.
Buchan, J. R., Kolaitis, R.-M., Taylor, J. P. and Parker, R. (2013). Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153, 1461–74.
Buchsbaum, S., Bercovich, B. and Ciechanover, A. (2012a). FAT10 is a proteasomal degradation signal that is itself regulated by ubiquitination. Mol. Biol. Cell 23, 225–32.
Buchsbaum, S., Bercovich, B., Ziv, T. and Ciechanover, A. (2012b). Modification of the inflammatory mediator LRRFIP2 by the ubiquitin-like protein FAT10 inhibits its activity during cellular response to LPS. Biochem. Biophys. Res. Commun. 428, 11–6.
Buerger, S. (2013). The Ubiquitin-like modifier FAT10 in tolerance induction. Univ. Konstanz, Dr. thesis.
Burroughs, A. M., Jaffee, M., Iyer, L. M. and Aravind, L. (2008). Anatomy of the E2 ligase fold:
implications for enzymology and evolution of ubiquitin/Ub-like protein conjugation. J. Struct. Biol. 162, 205–18.
Cai, Z. P., Shen, Z., Van Kaer, L. and Becker, L. C. (2008). Ischemic preconditioning-induced cardioprotection is lost in mice with immunoproteasome subunit low molecular mass polypeptide-2 deficiency. FASEB J. 22, 4248–57.
Canaan, A., Yu, X., Booth, C. and Lian, J. (2006). FAT10/diubiquitin-like protein-deficient mice exhibit minimal phenotypic differences. Mol. Cell. Biol. 26, 5180–5189.
Canaan, A., DeFuria, J., Perelman, E., Schultz, V., Seay, M., Tuck, D., Flavell, R. a., Snyder, M. P., Obin, M. S. and Weissman, S. M. (2014). Extended lifespan and reduced adiposity in mice lacking the FAT10 gene. Proc. Natl. Acad. Sci. 1–6.
Canadien, V., Tan, T., Zilber, R., Szeto, J., Perrin, A. J. and Brumell, J. H. (2005). Cutting edge: microbial products elicit formation of dendritic cell aggresome-like induced structures in macrophages. J. Immunol.
174, 2471–5.
Caplen, N. J., Parrish, S., Imani, F., Fire, A. and Morgan, R. A. (2001). Specific inhibition of gene
expression by small double-stranded RNAs in invertebrate and vertebrate systems. Proc. Natl. Acad. Sci.
U. S. A. 98, 9742–7.
138
Carlson, N. and Rechsteiner, M. (1987). Microinjection of ubiquitin: intracellular distribution and metabolism in HeLa cells maintained under normal physiological conditions. J. Cell Biol. 104, 537–46.
Cascio, P., Call, M., Petre, B. M., Walz, T. and Goldberg, A. L. (2002). Properties of the hybrid form of the 26S proteasome containing both 19S and PA28 complexes. EMBO J. 21, 2636–45.
Castellanos-Rubio, A., Santin, I., Irastorza, I., Sanchez-Valverde, F., Castaño, L., Vitoria, J. C. and Bilbao, J. R. (2010). A regulatory single nucleotide polymorphism in the ubiquitin D gene associated with celiac disease. Hum. Immunol. 71, 96–9.
Cavey, J. R., Ralston, S. H., Hocking, L. J., Sheppard, P. W., Ciani, B., Searle, M. S. and Layfield, R.
(2005). Loss of ubiquitin-binding associated with Paget’s disease of bone p62 (SQSTM1) mutations. J.
Bone Miner. Res. 20, 619–24.
Cemma, M., Kim, P. K. and Brumell, J. H. (2011). The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway. Autophagy 7, 341–5.
Chen, W., Norbury, C. C., Cho, Y., Yewdell, J. W. and Bennink, J. R. (2001). Immunoproteasomes shape immunodominance hierarchies of antiviral CD8(+) T cells at the levels of T cell repertoire and
presentation of viral antigens. J. Exp. Med. 193, 1319–26.
Chen, X., Barton, L. F., Chi, Y., Clurman, B. E. and Roberts, J. M. (2007). Ubiquitin-independent degradation of cell-cycle inhibitors by the REGgamma proteasome. Mol. Cell 26, 843–52.
Chen, J., Yang, L., Chen, H., Yuan, T., Liu, M. and Chen, P. (2014). Recombinant adenovirus encoding FAT10 small interfering RNA inhibits HCC growth in vitro and in vivo. Exp. Mol. Pathol. 96, 207–211.
Chiu, Y., Sun, Q. and Chen, Z. (2007). E1-L2 activates both ubiquitin and FAT10. Mol. Cell 27, 1014–1023.
Choi, A. M. K., Ryter, S. W. and Levine, B. (2013). Autophagy in human health and disease. N. Engl. J. Med.
368, 651–62.
Choi, Y., Kim, J. K. and Yoo, J.-Y. (2014). NFκB and STAT3 synergistically activate the expression of FAT10, a gene counteracting the tumor suppressor p53. Mol. Oncol. 1–14.
Ciechanover, A. and Stanhill, A. (2014). The complexity of recognition of ubiquitinated substrates by the 26S proteasome. Biochim. Biophys. Acta 1843, 86–96.
Ciechanover, A., Heller, H., Elias, S., Haas, A. L. and Hershko, A. (1980). ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation. Proc. Natl. Acad. Sci. 77, 1365–1368.
Conway, K. L., Kuballa, P., Song, J.-H., Patel, K. K., Castoreno, A. B., Yilmaz, O. H., Jijon, H. B., Zhang, M., Aldrich, L. N., Villablanca, E. J., et al. (2013). Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 145, 1347–57.
Coux, O., Tanaka, K. and Goldberg, A. L. (1996). Structure and functions of the 20S and 26S proteasomes.
Annu. Rev. Biochem. 65, 801–47.
Cruz, M., Elenich, L. A., Smolarek, T. A., Menon, A. G. and Monaco, J. J. (1997). DNA sequence, chromosomal localization, and tissue expression of the mouse proteasome subunit lmp10 (Psmb10) gene.
Genomics 45, 618–22.
d’Ydewalle, C., Bogaert, E. and Van Den Bosch, L. (2012). HDAC6 at the Intersection of Neuroprotection and Neurodegeneration. Traffic 13, 771–9.
139
Dahlmann, B., Ruppert, T., Kuehn, L., Merforth, S. and Kloetzel, P. M. (2000). Different proteasome subtypes in a single tissue exhibit different enzymatic properties. J. Mol. Biol. 303, 643–53.
Dammer, E. B., Na, C. H., Xu, P., Seyfried, N. T., Duong, D. M., Cheng, D., Gearing, M., Rees, H., Lah, J.
J., Levey, A. I., et al. (2011). Polyubiquitin linkage profiles in three models of proteolytic stress suggest the etiology of Alzheimer disease. J. Biol. Chem. 286, 10457–65.
De, M., Jayarapu, K., Elenich, L., Monaco, J. J., Colbert, R. A. and Griffin, T. A. (2003). Beta 2 subunit propeptides influence cooperative proteasome assembly. J. Biol. Chem. 278, 6153–9.
Decker, T., Stockinger, S., Karaghiosoff, M., Müller, M. and Kovarik, P. (2002). IFNs and STATs in innate immunity to microorganisms. J. Clin. Invest. 109, 1271–7.
Delgado, M. A., Elmaoued, R. A., Davis, A. S., Kyei, G. and Deretic, V. (2008). Toll-like receptors control autophagy. EMBO J. 27, 1110–21.
Deol, P., Zaiss, D. M. W., Monaco, J. J. and Sijts, A. J. A. M. (2007). Rates of Processing Determine the Immunogenicity of Immunoproteasome-Generated Epitopes. J. Immunol. 178, 7557–7562.
Djavaheri-Mergny, M., Amelotti, M., Mathieu, J., Besancon, F., Bauvy, C., Souquere, S., Pierron, G. and Codogno, P. (2006). NF- B Activation Represses Tumor Necrosis Factor- -induced Autophagy. J. Biol.
Chem. 281, 30373–30382.
Dokmanovic, M., Chang, B.-D., Fang, J. and Roninson, I. B. (2002). Retinoid-induced growth arrest of breast carcinoma cells involves co-activation of multiple growth-inhibitory genes. Cancer Biol. Ther. 1, 24–7.
Dong, X. and Levine, B. (2013). Autophagy and viruses: adversaries or allies? J. Innate Immun. 5, 480–93.
Dortet, L., Mostowy, S., Samba-Louaka, A., Louaka, A. S., Gouin, E., Nahori, M.-A., Wiemer, E. A. C., Dussurget, O. and Cossart, P. (2011). Recruitment of the major vault protein by InlK: a Listeria monocytogenes strategy to avoid autophagy. PLoS Pathog. 7, e1002168.
Downes, B. P., Saracco, S. A., Lee, S. S., Crowell, D. N. and Vierstra, R. D. (2006). MUBs, a family of ubiquitin-fold proteins that are plasma membrane-anchored by prenylation. J. Biol. Chem. 281, 27145–57.
Drews, O., Wildgruber, R., Zong, C., Sukop, U., Nissum, M., Weber, G., Gomes, A. V and Ping, P. (2007).
Mammalian proteasome subpopulations with distinct molecular compositions and proteolytic activities.
Mol. Cell. Proteomics 6, 2021–31.
Dunn, W. A., Cregg, J. M., Kiel, J. A. K. W., van der Klei, I. J., Oku, M., Sakai, Y., Sibirny, A. A., Stasyk, O. V and Veenhuis, M. (2005). Pexophagy: the selective autophagy of peroxisomes. Autophagy 1, 75–83.
Dunstan, S. J., Ho, V. A., Duc, C. M., Lanh, M. N., Phuong, C. X., Luxemburger, C., Wain, J., Dudbridge, F., Peacock, C. S., House, D., et al. (2001). Typhoid fever and genetic polymorphisms at the natural resistance-associated macrophage protein 1. J. Infect. Dis. 183, 1156–60.
Dupont, N., Lacas-Gervais, S., Bertout, J., Paz, I., Freche, B., Van Nhieu, G. T., van der Goot, F. G., Sansonetti, P. J. and Lafont, F. (2009). Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy. Cell Host Microbe 6, 137–49.
Durán, A., Serrano, M., Leitges, M., Flores, J. M., Picard, S., Brown, J. P., Moscat, J. and Diaz-Meco, M.
T. (2004). The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev. Cell 6, 303–9.
Durfee, L. A., Lyon, N., Seo, K. and Huibregtse, J. M. (2010). The ISG15 conjugation system broadly targets newly synthesized proteins: implications for the antiviral function of ISG15. Mol. Cell 38, 722–32.
140
Ebstein, F., Lehmann, A. and Kloetzel, P.-M. (2012). The FAT10- and ubiquitin-dependent degradation
Ebstein, F., Lehmann, A. and Kloetzel, P.-M. (2012). The FAT10- and ubiquitin-dependent degradation