Activity-based probes for the ubiquitin conjugation–deconjugation machinery: new chemistries, new tools, and new insights

FEBS Journal

Volumn 284, Issue 10, 2017, Pages 1555-1576

  Hewings, David S ^a,b   Flygare, John A ^a,c   Bogyo, Matthew ^b   Wertz, Ingrid E ^a  

^a GENENTECH INC   (United States)

^b STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c MERCK RESEARCH LABORATORIES   (United States)

Author keywords

activity based probe; activity based protein profiling; chemoproteomics; deubiquitinase; E1; E3; protease; ubiquitin; ubiquitin proteasome system

Indexed keywords

DEUBIQUITINASE; DIUBIQUITIN; JAMM PROTEIN; METALLOPROTEINASE; MONO UBIQUITIN; UBIQUITIN; UBIQUITIN CONJUGATING ENZYME E2; UBIQUITIN LIKE PROTEIN PROTEASE; UBIQUITIN PROTEIN LIGASE; UBIQUITIN PROTEIN LIGASE E3; UNCLASSIFIED DRUG; PEPTIDE HYDROLASE; PROTEASOME;

AMINO TERMINAL SEQUENCE; CARBOXY TERMINAL SEQUENCE; CELL MEMBRANE PERMEABILITY; CONJUGATION; DECONJUGATION; ENZYME ACTIVITY; ENZYME SUBSTRATE; HUMAN; LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY; MASS SPECTROMETRY; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; QUANTITATIVE ANALYSIS; REVIEW; UBIQUITINATION; ANIMAL; METABOLISM; PROTEIN PROCESSING;

ANIMALS; DEUBIQUITINATING ENZYMES; HUMANS; PEPTIDE HYDROLASES; PROTEASOME ENDOPEPTIDASE COMPLEX; PROTEIN PROCESSING, POST-TRANSLATIONAL; UBIQUITIN; UBIQUITIN-SPECIFIC PROTEASES;

EID: 85015042001     PISSN: 1742464X     EISSN: 17424658     Source Type: Journal    
DOI: 10.1111/febs.14039     Document Type: Review

References (123)

1. Hershko A & Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67, 425–479.
2. Wilkinson KD (2005) The discovery of ubiquitin-dependent proteolysis. Proc Nat Acad Sci USA 102, 15280–15282.
3. Ikeda F & Dikic I (2008) Atypical ubiquitin chains: new molecular signals. “Protein Modifications: Beyond the Usual Suspects” review series. EMBO Rep 9, 536–542.
4. Komander D (2009) The emerging complexity of protein ubiquitination. Biochem Soc Trans 37, 937–953.
5. Peng J, Schwartz D, Elias JE, Thoreen CC, Cheng D, Marsischky G, Roelofs J, Finley D & Gygi SP (2003) A proteomics approach to understanding protein ubiquitination. Nat Biotechnol 21, 921–926.
6. Chau V, Tobias JW, Bachmair A, Marriott D, Ecker DJ, Gonda DK & Varshavsky A (1989) A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243, 1576–1583.
7. Hu H & Sun S-C (2016) Ubiquitin signaling in immune responses. Cell Res 26, 457–483.
8. Shimizu Y, Taraborrelli L & Walczak H (2015) Linear ubiquitination in immunity. Immunol Rev 266, 190–207.
9. Herrmann J, Lerman LO & Lerman A (2007) Ubiquitin and ubiquitin-like proteins in protein regulation. Circ Res 100, 1276–1291.
10. Hemelaar J, Lelyveld VS, Kessler BM & Ploegh HL (2003) A single protease, Apg4B, is specific for the autophagy-related ubiquitin-like proteins GATE-16, MAP1-LC3, GABARAP, and Apg8L. J Biol Chem 278, 51841–51850.
11. Maupin-Furlow JA (2014) Prokaryotic ubiquitin-like protein modification. Annu Rev Microbiol 68, 155–175.
12. Pearce MJ, Mintseris J, Ferreyra J, Gygi SP & Darwin KH (2008) Ubiquitin-like protein involved in the proteasome pathway of Mycobacterium tuberculosis. Science 322, 1104–1107.
13. Scheffner M & Kumar S (2014) Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects. Biochim Biophys Acta 1843, 61–74.
14. Berndsen CE & Wolberger C (2014) New insights into ubiquitin E3 ligase mechanism. Nat Struct Mol Biol 21, 301–307.
15. Heideker J & Wertz IE (2015) DUBs, the regulation of cell identity and disease. Biochem J 465, 1–26.
16. Grou CP, Pinto MP, Mendes AV, Domingues P & Azevedo JE (2015) The de novo synthesis of ubiquitin: identification of deubiquitinases acting on ubiquitin precursors. Sci Rep 5, 12836.
17. Lee MJ, Lee B-H, Hanna J, King RW & Finley D (2011) Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes. Mol Cell Proteomics 10, R110.003871–R1111000387.
18. Komander D, Clague MJ & Urbé S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10, 550–563.
19. Abdul Rehman SA, Kristariyanto YA, Choi S-Y, Nkosi PJ, Weidlich S, Labib K, Hofmann K & Kulathu Y (2016) MINDY-1 is a member of an evolutionarily conserved and structurally distinct new family of deubiquitinating enzymes. Mol Cell 63, 146–155.
20. Ito T & Handa H (2016) Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs. Int J Hematol 104, 293–299.
21. Kojima K, Ishizawa J & Andreeff M (2016) Pharmacological activation of wild-type p53 in the therapy of leukemia. Exp Hematol 44, 791–798.
22. Fulda S (2015) Promises and challenges of Smac mimetics as cancer therapeutics. Clin Cancer Res 21, 5030–5036.
23. Sanman LE & Bogyo M (2014) Activity-based profiling of proteases. Annu Rev Biochem 83, 249–273.
24. Prescher JA & Bertozzi CR (2005) Chemistry in living systems. Nat Chem Biol 1, 13–21.
25. Cravatt BF, Wright AT & Kozarich JW (2008) Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu Rev Biochem 77, 383–414.
26. Borodovsky A, Kessler BM, Casagrande R, Overkleeft HS, Wilkinson KD & Ploegh HL (2001) A novel active site-directed probe specific for deubiquitylating enzymes reveals proteasome association of USP14. EMBO J 20, 5187–5196.
27. Gopinath P, Ohayon S, Nawatha M & Brik A (2016) Chemical and semisynthetic approaches to study and target deubiquitinases. Chem Soc Rev 45, 4171–4198.
28. Hameed DS, Sapmaz A & Ovaa H (2016) How chemical synthesis of ubiquitin conjugates helps to understand ubiquitin signal transduction. Bioconjugate Chem. doi: 10.1021/acs.bioconjchem.6b00140.
29. van Tilburg GB, Elhebieshy AF & Ovaa H (2016) Synthetic and semi-synthetic strategies to study ubiquitin signaling. Curr Opin Struct Biol 38, 92–101.
30. Weller CE, Pilkerton ME & Chatterjee C (2014) Chemical strategies to understand the language of ubiquitin signaling. Biopolymers 101, 144–155.
31. Ward JA, McLellan L, Stockley M, Gibson KR, Whitlock GA, Knights C, Harrigan JA, Jacq X & Tate EW (2016) Quantitative chemical proteomic profiling of ubiquitin specific proteases in intact cancer cells. ACS Chem Biol 11, 3268–3272.
32. Borodovsky A, Ovaa H, Kolli N & Gan-Erdene T (2002) Chemistry-based functional proteomics reveals novel members of the deubiquitinating enzyme family. Chem Biol 9, 1149–1159.
33. Lam YA, Xu W, DeMartino GN & Cohen RE (1997) Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome. Nature 385, 737–740.
34. Pickart CM & Rose IA (1986) Mechanism of ubiquitin carboxyl-terminal hydrolase. Borohydride and hydroxylamine inactivate in the presence of ubiquitin. J Biol Chem 261, 10210–10217.
35. Hershko A & Rose IA (1987) Ubiquitin-aldehyde: a general inhibitor of ubiquitin-recycling processes. Proc Nat Acad Sci USA 84, 1829–1833.
36. Johnston SC, Riddle SM, Cohen RE & Hill CP (1999) Structural basis for the specificity of ubiquitin C-terminal hydrolases. EMBO J 18, 3877–3887.
37. Hemelaar J, Borodovsky A, Kessler BM, Reverter D, Cook J, Kolli N, Gan-Erdene T, Wilkinson KD, Gill G, Lima CD et al. (2004) Specific and covalent targeting of conjugating and deconjugating enzymes of ubiquitin-like proteins. Mol Cell Biol 24, 84–95.
38. Ekkebus R, van Kasteren SI, Kulathu Y, Scholten A, Berlin I, Geurink PP, de Jong A, Goerdayal S, Neefjes J, Heck AJR et al. (2013) On terminal alkynes that can react with active-site cysteine nucleophiles in proteases. J Am Chem Soc 135, 2867–2870.
39. Sommer S, Weikart ND, Linne U & Mootz HD (2013) Covalent inhibition of SUMO and ubiquitin-specific cysteine proteases by an in situ thiol-alkyne addition. Bioorg Med Chem 21, 2511–2517.
40. Arkona C & Rademann J (2013) Propargyl amides as irreversible inhibitors of cysteine proteases–a lesson on the biological reactivity of alkynes. Angew Chem Int Ed Engl 52, 8210–8212.
41. An H & Statsyuk AV (2013) Development of activity-based probes for ubiquitin and ubiquitin-like protein signaling pathways. J Am Chem Soc 135, 16948–16962.
42. Love KR, Pandya RK, Spooner E & Ploegh HL (2009) Ubiquitin C-terminal electrophiles are activity-based probes for identification and mechanistic study of ubiquitin conjugating machinery. ACS Chem Biol 4, 275–287.
43. Albrow VE, Ponder EL, Fasci D, Békés M, Deu E, Salvesen GS & Bogyo M (2011) Development of small molecule inhibitors and probes of human SUMO deconjugating proteases. Chem Biol 18, 722–732.
44. Dobrotă C, Fasci D, Hădade ND, Roiban GD, Pop C, Meier VM, Dumitru I, Matache M, Salvesen GS & Funeriu DP (2012) Glycine fluoromethylketones as SENP-specific activity based probes. ChemBioChem 13, 80–84.
45. Lee J-G, Baek K, Soetandyo N & Ye Y (2013) Reversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells. Nat Commun 4, 1568.
46. Cotto-Rios XM, Békés M, Chapman J, Ueberheide B & Huang TT (2012) Deubiquitinases as a signaling target of oxidative stress. Cell Rep 2, 1475–1484.
47. Naik E & Dixit VM (2016) Usp9X is required for lymphocyte activation and homeostasis through its control of ZAP70 ubiquitination and PKCβ kinase activity. J Immunol 196, 3438–3451.
48. Wang T, Yin L, Cooper EM, Lai M-Y, Dickey S, Pickart CM, Fushman D, Wilkinson KD, Cohen RE & Wolberger C (2009) Evidence for bidentate substrate binding as the basis for the K48 linkage specificity of otubain 1. J Mol Biol 386, 1011–1023.
49. Balakirev MY, Jaquinod M, Haas AL & Chroboczek J (2002) Deubiquitinating function of adenovirus proteinase. J Virol 76, 6323–6331.
50. Gan-Erdene T, Nagamalleswari K, Yin L, Wu K, Pan Z-Q & Wilkinson KD (2003) Identification and characterization of DEN1, a deneddylase of the ULP family. J Biol Chem 278, 28892–28900.
51. Altun M, Kramer HB, Willems LI, McDermott JL, Leach CA, Goldenberg SJ, Kumar KGS, Konietzny R, Fischer R, Kogan E et al. (2011) Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. Chem Biol 18, 1401–1412.
52. Lill JR & Wertz IE (2014) Toward understanding ubiquitin-modifying enzymes: from pharmacological targeting to proteomics. Trends Pharmacol Sci 35, 187–207.
53. McGouran JF, Kramer HB, Mackeen MM, di Gleria K, Altun M & Kessler BM (2012) Fluorescence-based active site probes for profiling deubiquitinating enzymes. Org Biomol Chem 10, 3379–3383.
54. de Jong A, Merkx R, Berlin I, Rodenko B, Wijdeven RHM, El Atmioui D, Yalçin Z, Robson CN, Neefjes JJ & Ovaa H (2012) Ubiquitin-based probes prepared by total synthesis to profile the activity of deubiquitinating enzymes. ChemBioChem 13, 2251–2258.
55. Claessen JHL, Witte MD, Yoder NC, Zhu AY, Spooner E & Ploegh HL (2013) Catch-and-release probes applied to semi-intact cells reveal ubiquitin-specific protease expression in Chlamydia trachomatis infection. ChemBioChem 14, 343–352.
56. Ronau JA, Beckmann JF & Hochstrasser M (2016) Substrate specificity of the ubiquitin and Ubl proteases. Cell Res 26, 441–456.
57. Renatus M, Parrado SG, D'Arcy A, Eidhoff U, Gerhartz B, Hassiepen U, Pierrat B, Riedl R, Vinzenz D, Worpenberg S et al. (2006) Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. Structure 14, 1293–1302.
58. Hu M, Li P, Li M, Li W, Yao T, Wu J-W, Gu W, Cohen RE & Shi Y (2002) Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell 111, 1041–1054.
59. Hu M, Li P, Song L, Jeffrey PD, Chernova TA, Wilkinson KD, Cohen RE & Shi Y (2005) Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14. EMBO J 24, 3747–3756.
60. Borodovsky A, Ovaa H, Meester WJN, Venanzi ES, Bogyo MS, Hekking BG, Ploegh HL, Kessler BM & Overkleeft HS (2005) Small-molecule inhibitors and probes for ubiquitin- and ubiquitin-like-specific proteases. ChemBioChem 6, 287–291.
61. Mulder MPC, Witting K, Berlin I, Pruneda JN, Wu K-P, Chang J-G, Merkx R, Bialas J, Groettrup M, Vertegaal ACO et al. (2016) A cascading activity-based probe sequentially targets E1-E2-E3 ubiquitin enzymes. Nat Chem Biol 12, 523–530.
62. Iphöfer A, Kummer A, Nimtz M, Ritter A, Arnold T, Frank R, van den Heuvel J, Kessler BM, Jänsch L & Franke R (2012) Profiling ubiquitin linkage specificities of deubiquitinating enzymes with branched ubiquitin isopeptide probes. ChemBioChem 13, 1416–1420.
63. Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB, Kulathu Y, Wauer T, Hospenthal MK, Gyrd-Hansen M, Krappmann D et al. (2013) OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell 153, 1312–1326.
64. Li G, Liang Q, Gong P, Tencer AH & Zhuang Z (2013) Activity-based diubiquitin probes for elucidating the linkage specificity of deubiquitinating enzymes. Chem Commun 50, 216–218.
65. McGouran JF, Gaertner SR, Altun M, Kramer HB & Kessler BM (2013) Deubiquitinating enzyme specificity for ubiquitin chain topology profiled by di-ubiquitin activity probes. Chem Biol 20, 1447–1455.
66. Haj-Yahya N, Hemantha HP, Meledin R, Bondalapati S, Seenaiah M & Brik A (2014) Dehydroalanine-based diubiquitin activity probes. Org Lett 16, 540–543.
67. Flierman D, van der Heden van Noort GJ, Ekkebus R, Geurink PP, Mevissen TET, Hospenthal MK, Komander D & Ovaa H (2016) Non-hydrolyzable diubiquitin probes reveal linkage-specific reactivity of deubiquitylating enzymes mediated by S2 pockets. Cell Chem Biol 23, 472–482.
68. Mulder MPC, El Oualid F, ter Beek J & Ovaa H (2014) A native chemical ligation handle that enables the synthesis of advanced activity-based probes: diubiquitin as a case study. ChemBioChem 15, 946–949.
69. Misaghi S, Galardy PJ, Meester WJN, Ovaa H, Ploegh HL & Gaudet R (2005) Structure of the ubiquitin hydrolase UCH-L3 complexed with a suicide substrate. J Biol Chem 280, 1512–1520.
70. Balakirev MY, Tcherniuk SO, Jaquinod M & Chroboczek J (2003) Otubains: a new family of cysteine proteases in the ubiquitin pathway. EMBO Rep 4, 517–522.
71. Kattenhorn LM, Korbel GA, Kessler BM, Spooner E & Ploegh HL (2005) A deubiquitinating enzyme encoded by HSV-1 belongs to a family of cysteine proteases that is conserved across the family Herpesviridae. Mol Cell 19, 547–557.
72. Schlieker C, Korbel GA, Kattenhorn LM & Ploegh HL (2005) A deubiquitinating activity is conserved in the large tegument protein of the herpesviridae. J Virol 79, 15582–15585.
73. Misaghi S, Balsara ZR, Catic A, Spooner E, Ploegh HL & Starnbach MN (2006) Chlamydia trachomatis-derived deubiquitinating enzymes in mammalian cells during infection. Mol Microbiol 61, 142–150.
74. Sheedlo MJ, Qiu J, Tan Y, Paul LN, Luo Z-Q & Das C (2015) Structural basis of substrate recognition by a bacterial deubiquitinase important for dynamics of phagosome ubiquitination. Proc Nat Acad Sci USA 112, 15090–15095.
75. Catic A, Misaghi S, Korbel GA & Ploegh HL (2007) ElaD, a deubiquitinating protease expressed by E. coli. PLoS One 2, e381.
76. Frickel E-M, Quesada V, Muething L, Gubbels M-J, Spooner E, Ploegh H & Artavanis-Tsakonas K (2007) Apicomplexan UCHL3 retains dual specificity for ubiquitin and Nedd8 throughout evolution. Cell Microbiol 9, 1601–1610.
77. Artavanis-Tsakonas K, Misaghi S, Comeaux CA, Catic A, Spooner E, Duraisingh MT & Ploegh HL (2006) Identification by functional proteomics of a deubiquitinating/deNeddylating enzyme in Plasmodium falciparum. Mol Microbiol 61, 1187–1195.
78. White RR, Miyata S, Papa E, Spooner E, Gounaris K, Selkirk ME & Artavanis-Tsakonas K (2011) Characterisation of the Trichinella spiralis deubiquitinating enzyme, TsUCH37, an evolutionarily conserved proteasome interaction partner. PLoS Negl Trop Dis 5, e1340.
79. Ponder EL & Bogyo M (2007) Ubiquitin-like modifiers and their deconjugating enzymes in medically important parasitic protozoa. Eukaryot Cell 6, 1943–1952.
80. Pruneda JN, Durkin CH, Geurink PP, Ovaa H, Santhanam B, Holden DW & Komander D (2016) The molecular basis for ubiquitin and ubiquitin-like specificities in bacterial effector proteases. Mol Cell 63, 261–276.
81. Geurink PP, El Oualid F, Jonker A, Hameed DS & Ovaa H (2012) A general chemical ligation approach towards isopeptide-linked ubiquitin and ubiquitin-like assay reagents. ChemBioChem 13, 293–297.
82. Ritorto MS, Ewan R, Perez-Oliva AB, Knebel A, Buhrlage SJ, Wightman M, Kelly SM, Wood NT, Virdee S, Gray NS et al. (2014) Screening of DUB activity and specificity by MALDI-TOF mass spectrometry. Nat Commun 5, 4763.
83. Mevissen TET, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F et al. (2013) OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell 154, 169–184.
84. Mevissen TET, Kulathu Y, Mulder MPC, Geurink PP, Maslen SL, Gersch M, Elliott PR, Burke JE, van Tol BDM, Akutsu M et al. (2016) Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne. Nature 538, 402–405.
85. Békés M, Rut W, Kasperkiewicz P, Mulder MPC, Ovaa H, Drag M, Lima CD & Huang TT (2015) SARS hCoV papain-like protease is a unique Lys48 linkage-specific di-distributive deubiquitinating enzyme. Biochem J 468, 215–226.
86. Békés M, van der Heden van Noort GJ, Ekkebus R, Ovaa H, Huang TT & Lima CD (2016) Recognition of Lys48-linked di-ubiquitin and deubiquitinating activities of the SARS coronavirus papain-like protease. Mol Cell 62, 572–585.
87. Ovaa H, Kessler BM, Rolen U, Galardy PJ, Ploegh HL & Masucci MG (2004) Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. Proc Nat Acad Sci USA 101, 2253–2258.
88. Rolén U, Kobzeva V, Gasparjan N, Ovaa H, Winberg G, Kisseljov F & Masucci MG (2006) Activity profiling of deubiquitinating enzymes in cervical carcinoma biopsies and cell lines. Mol Carcinog 45, 260–269.
89. Gao Y, Koppen A, Rakhshandehroo M, Tasdelen I, van de Graaf SF, van Loosdregt J, van Beekum O, Hamers N, van Leenen D, Berkers CR et al. (2013) Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60. Nat Commun 4, 2656.
90. Kummari E, Alugubelly N, Hsu C-Y, Dong B, Nanduri B & Edelmann MJ (2015) Activity-based proteomic profiling of deubiquitinating enzymes in salmonella-infected macrophages leads to identification of putative function of UCH-L5 in inflammasome regulation. PLoS One 10, e0135531.
91. Lopez-Castejon G, Luheshi NM, Compan V, High S, Whitehead RC, Flitsch S, Kirov A, Prudovsky I, Swanton E & Brough D (2013) Deubiquitinases regulate the activity of caspase-1 and interleukin-1β secretion via assembly of the inflammasome. J Biol Chem 288, 2721–2733.
92. Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q, Foreman O, Kirkpatrick DS & Sheng M (2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375.
93. Aressy B, Jullien D, Cazales M, Marcellin M, Bugler B, Burlet-Schiltz O & Ducommun B (2010) A screen for deubiquitinating enzymes involved in the G2/M checkpoint identifies USP50 as a regulator of HSP90-dependent Wee1 stability. Cell Cycle 9, 3839–3846.
94. Dar A, Shibata E & Dutta A (2013) Deubiquitination of Tip60 by USP7 determines the activity of the p53-dependent apoptotic pathway. Mol Cell Biol 33, 3309–3320.
95. Py BF, Kim M-S, Vakifahmetoglu-Norberg H & Yuan J (2013) Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell 49, 331–338.
96. Kramer HB, Nicholson B, Kessler BM & Altun M (2012) Detection of ubiquitin-proteasome enzymatic activities in cells: application of activity-based probes to inhibitor development. Biochim Biophys Acta 1823, 2029–2037.
97. Reverdy C, Conrath S, Lopez R, Planquette C, Atmanene C, Collura V, Harpon J, Battaglia V, Vivat V, Sippl W et al. (2012) Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme. Chem Biol 19, 467–477.
98. Wang X, Mazurkiewicz M, Hillert E-K, Olofsson MH, Pierrou S, Hillertz P, Gullbo J, Selvaraju K, Paulus A, Akhtar S et al. (2016) The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Sci Rep 6, 26979.
99. Berndtsson M, Beaujouin M, Rickardson L, Havelka AM, Larsson R, Westman J, Liaudet Coopman E & Linder S (2009) Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system. Int J Cancer 124, 1463–1469.
100. D'Arcy P, Brnjic S, Olofsson MH, Fryknäs M, Lindsten K, De Cesare M, Perego P, Sadeghi B, Hassan M, Larsson R et al. (2011) Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med 17, 1636–1640.
101. Wang X, D'Arcy P, Caulfield TR, Paulus A, Chitta K, Mohanty C, Gullbo J, Chanan Khan A & Linder S (2015) Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15. Chem Biol Drug Des 86, 1036–1048.
102. Wang X, Stafford W, Mazurkiewicz M, Fryknäs M, Brjnic S, Zhang X, Gullbo J, Larsson R, Arnér ESJ, D'Arcy P et al. (2014) The 19S Deubiquitinase inhibitor b-AP15 is enriched in cells and elicits rapid commitment to cell death. Mol Pharmacol 85, 932–945.
103. D'Arcy P, Wang X & Linder S (2015) Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther 147, 32–54.
104. Ndubaku C & Tsui V (2015) Inhibiting the deubiquitinating enzymes (DUBs). J Med Chem 58, 1581–1595.
105. Farshi P, Deshmukh RR, Nwankwo JO, Arkwright RT, Cvek B, Liu J & Dou QP (2015) Deubiquitinases (DUBs) and DUB inhibitors: a patent review. Expert Opin Ther Pat 25, 1191–1208.
106. Kemp M (2016) Recent advances in the discovery of deubiquitinating enzyme inhibitors. In Progress in Medicinal Chemistry (Lawton G & Witty DR, eds), pp. 149–192. Elsevier, Amsterdam.
107. Olsen SK, Capili AD, Lu X, Tan DS & Lima CD (2010) Active site remodelling accompanies thioester bond formation in the SUMO E1. Nature 463, 906–912.
108. Lu X, Olsen SK, Capili AD, Cisar JS, Lima CD & Tan DS (2010) Designed semisynthetic protein inhibitors of Ub/Ubl E1 activating enzymes. J Am Chem Soc 132, 1748–1749.
109. An H & Statsyuk AV (2016) Facile synthesis of covalent probes to capture enzymatic intermediates during E1 enzyme catalysis. Chem Commun 52, 2477–2480.
110. Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S et al. (2009) An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458, 732–736.
111. An H & Statsyuk AV (2015) An inhibitor of ubiquitin conjugation and aggresome formation. Chem Sci 6, 5235–5245.
112. Fonović M, Verhelst SHL, Sorum MT & Bogyo M (2007) Proteomics evaluation of chemically cleavable activity-based probes. Mol Cell Proteomics 6, 1761–1770.
113. Yang Y, Hahne H, Kuster B & Verhelst SHL (2013) A simple and effective cleavable linker for chemical proteomics applications. Mol Cell Proteomics 12, 237–244.
114. Stanley M, Han C, Knebel A, Murphy P, Shpiro N & Virdee S (2015) Orthogonal thiol functionalization at a single atomic center for profiling transthiolation activity of E1 activating enzymes. ACS Chem Biol 10, 1542–1554.
115. Pao K-C, Stanley M, Han C, Lai Y-C, Murphy P, Balk K, Wood NT, Corti O, Corvol J-C, Muqit MMK et al. (2016) Probes of ubiquitin E3 ligases enable systematic dissection of parkin activation. Nat Chem Biol 12, 324–331.
116. Zhang Y, Zhou L, Rougé L, Phillips AH, Lam C, Liu P, Sandoval W, Helgason E, Murray JM, Wertz IE et al. (2012) Conformational stabilization of ubiquitin yields potent and selective inhibitors of USP7. Nat Chem Biol 9, 51–58.
117. Ernst A, Avvakumov G, Tong J, Fan Y, Zhao Y, Alberts P, Persaud A, Walker JR, Neculai A-M, Neculai D et al. (2013) A strategy for modulation of enzymes in the ubiquitin system. Science 339, 590–595.
118. Damgaard RB, Walker JA, Marco-Casanova P, Morgan NV, Titheradge HL, Elliott PR, McHale D, Maher ER, McKenzie ANJ & Komander D (2016) The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell 166 (1215–1230), e20.
119. Elliott PR & Komander D (2016) Regulation of Met1-linked polyubiquitin signalling by the deubiquitinase OTULIN. FEBS J 283, 39–53.
120. Saghatelian A, Jessani N, Joseph A, Humphrey M & Cravatt BF (2004) Activity-based probes for the proteomic profiling of metalloproteases. Proc Nat Acad Sci USA 101, 10000–10005.
121. Morell M, Nguyen Duc T, Willis AL, Syed S, Lee J, Deu E, Deng Y, Xiao J, Turk BE, Jessen JR et al. (2013) Coupling protein engineering with probe design to inhibit and image matrix metalloproteinases with controlled specificity. J Am Chem Soc 135, 9139–9148.
122. Herhaus L & Dikic I (2015) Expanding the ubiquitin code through post-translational modification. EMBO Rep 16, 1071–1083.
123. Whedon SD, Markandeya N, Rana ASJB, Senger NA, Weller CE, Tureček F, Strieter ER & Chatterjee C (2016) Selenocysteine as a latent bioorthogonal electrophilic probe for deubiquitylating enzymes. J Am Chem Soc 138, 13774–13777.