Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

Abstract

BACKGROUND: The 26S proteasome is at the heart of the ubiquitin-proteasome system, which is the key cellular pathway for the regulated degradation of proteins and enforcement of protein quality control. The 26S proteasome is an unusually large and complicated protease comprising a 28-subunit core particle (CP) capped by one or two 19-subunit regulatory particles (RP). Multiple activities within the RP process incoming ubiquitinated substrates for eventual degradation by the barrel-shaped CP. The large size and elaborate architecture of the proteasome have made it an exceptional model for understanding mechanistic themes in macromolecular assembly.

OBJECTIVE: In the present work, we highlight the most recent mechanistic insights into proteasome assembly, with particular emphasis on intrinsic and extrinsic factors regulating proteasome biogenesis. We also describe new and exciting questions arising about how proteasome assembly is regulated and deregulated in normal and diseased cells.

METHODS: A comprehensive literature search using the PubMed search engine was performed, and key findings yielding mechanistic insight into proteasome assembly were included in this review.

RESULTS: Key recent studies have revealed that proteasome biogenesis is dependent upon intrinsic features of the subunits themselves as well as extrinsic factors, many of which function as dedicated chaperones.

CONCLUSION: Cells rely on a diverse set of mechanistic strategies to ensure the rapid, efficient, and faithful assembly of proteasomes from their cognate subunits. Importantly, physiological as well as pathological changes to proteasome assembly are emerging as exciting paradigms to alter protein degradation in vivo.

Key words： proteasome assembly; assembly chaperones; ubiquitin-proteasome system; proteolysis; macromolecular complex

Acknowledgements

The authors apologize to their colleagues whose work could not be discussed due to space limitations. This work was supported in part by start-up funds from the Florida State University College of Medicine (R.J.T.Jr.) and by a Research Support Funds Grant from Indiana University-Purdue University Indianapolis (A.R.K.).

Compliance with ethics guidelines

Lauren A. Howell, Robert J. Tomko Jr. and Andrew R. Kusmierczyk declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

References

1 Agarwal A K, Xing C, DeMartino G N, Mizrachi D, Hernandez M D, Sousa A B, Martínez de Villarreal L, dos Santos H G, Garg A (2010). PSMB8 encoding the beta5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet, 87(6): 866–872

2 Akahane T, Sahara K, Yashiroda H, Tanaka K, Murata S (2013). Involvement of Bag6 and the TRC pathway in proteasome assembly. Nat Commun, 4: 2234

3 Arendt C S, Hochstrasser M (1997). Identification of the yeast 20S proteasome catalytic centers and subunit interactions required for active-site formation. Proc Natl Acad Sci USA, 94(14): 7156–7161

4 Arendt C S, Hochstrasser M (1999). Eukaryotic 20S proteasome catalytic subunit propeptides prevent active site inactivation by N-terminal acetylation and promote particle assembly. EMBO J, 18(13): 3575–3585

5 Arima K, Kinoshita A, Mishima H, Kanazawa N, Kaneko T, Mizushima T, Ichinose K, Nakamura H, Tsujino A, Kawakami A, Matsunaka M, Kasagi S, Kawano S, Kumagai S, Ohmura K, Mimori T, Hirano M, Ueno S, Tanaka K, Tanaka M, Toyoshima I, Sugino H, Yamakawa A, Tanaka K, Niikawa N, Furukawa F, Murata S, Eguchi K, Ida H, Yoshiura K (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 USA, 108(36): 14914–14919

6 Asano S, Fukuda Y, Beck F, Aufderheide A, Forster F, Danev R, Baumeister W (2015). Proteasomes. A molecular census of 26S proteasomes in intact neurons. Science, 347(6220): 439–442

7 Aufderheide A, Beck F, Stengel F, Hartwig M, Schweitzer A, Pfeifer G, Goldberg A L, Sakata E, Baumeister W, Förster F (2015). Structural characterization of the interaction of Ubp6 with the 26S proteasome. Proc Natl Acad Sci USA, 112(28): 8626–8631

8 Bader M, Benjamin S, Wapinski O L, Smith D M, Goldberg A L, Steller H (2011). A conserved f box regulatory complex controls proteasome activity in Drosophila. Cell, 145(3): 371–382

9 Bai M, Zhao X, Sahara K, Ohte Y, Hirano Y, Kaneko T, Yashiroda H, Murata S (2014). Assembly mechanisms of specialized core particles of the proteasome. Biomolecules, 4(3): 662–677

10 Barrault M B, Richet N, Godard C, Murciano B, Le Tallec B, Rousseau E, Legrand P, Charbonnier J B, Le Du M H, Guerois R, Ochsenbein F, Peyroche A (2012). Dual functions of the Hsm3 protein in chaperoning and scaffolding regulatory particle subunits during the proteasome assembly. Proc Natl Acad Sci USA, 109(17): E1001–E1010

11 Barthelme D, Chen J Z, Grabenstatter J, Baker T A, Sauer R T (2014). Architecture and assembly of the archaeal Cdc48•20S proteasome. Proc Natl Acad Sci USA, 111(17): E1687–E1694

12 Barthelme D, Jauregui R, Sauer RT (2015). An ALS disease mutation in Cdc48/p97 impairs 20S proteasome binding and proteolytic communication. Protein Sci, 24:1521–1527

13 Barthelme D, Sauer R T (2012a). Identification of the Cdc48•20S proteasome as an ancient AAA+ proteolytic machine. Science, 337(6096): 843–846

14 Barthelme D, Sauer RT (2012b). Identification of the Cdc48•20S proteasome as an ancient AAA+ proteolytic machine. Science, 337(6096): 843–846

15 Barthelme D, Sauer R T (2013). Bipartite determinants mediate an evolutionarily conserved interaction between Cdc48 and the 20S peptidase. Proc Natl Acad Sci USA, 110(9): 3327–3332

16 Bashore C, Dambacher C M, Goodall E A, Matyskiela M E, Lander G C, Martin A (2015). Ubp6 deubiquitinase controls conformational dynamics and substrate degradation of the 26S proteasome. Nat Struct Mol Biol, 22(9): 712–719

17 Basler M, Kirk C J, Groettrup M (2013). The immunoproteasome in antigen processing and other immunological functions. Curr Opin Immunol, 25(1): 74–80

18 Beck F, Unverdorben P, Bohn S, Schweitzer A, Pfeifer G, Sakata E, Nickell S, Plitzko J M, Villa E, Baumeister W, Forster F (2012). Near-atomic resolution structural model of the yeast 26S proteasome. Proc Natl Acad Sci USA, 109(37): 14870–14875

19 Beckwith R, Estrin E, Worden E J, Martin A (2013). Reconstitution of the 26S proteasome reveals functional asymmetries in its AAA+ unfoldase. Nat Struct Mol Biol, 20(10): 1164–1172

20 Benaroudj N, Goldberg A L (2000). PAN, the proteasome-activating nucleotidase from archaebacteria, is a protein-unfolding molecular chaperone. Nat Cell Biol, 2(11): 833–839

21 Braun B C, Glickman M, Kraft R, Dahlmann B, Kloetzel P M, Finley D, Schmidt M (1999). The base of the proteasome regulatory particle exhibits chaperone-like activity. Nat Cell Biol, 1(4): 221–226

22 Burri L, Hockendorff J, Boehm U, Klamp T, Dohmen R J, Levy F (2000). Identification and characterization of a mammalian protein interacting with 20S proteasome precursors. Proc Natl Acad Sci USA, 97(19): 10348–10353

23 Cascio P (2014). PA28alphabeta: the enigmatic magic ring of the proteasome? Biomolecules, 4(2): 566–584

24 Chen P, Hochstrasser M (1996). Autocatalytic subunit processing couples active site formation in the 20S proteasome to completion of assembly. Cell, 86(6): 961–972

25 Chu-Ping M, Slaughter C A, DeMartino G N (1992). Purification and characterization of a protein inhibitor of the 20S proteasome (macropain). Biochim Biophys Acta, 1119(3): 303–311

26 Cohen-Kaplan V, Livneh I, Avni N, Fabre B, Ziv T, Kwon Y T, Ciechanover A (2016). p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome. Proc Natl Acad Sci USA, 113(47): E7490–E7499

27 Colot H V, Park G, Turner G E, Ringelberg C, Crew C M, Litvinkova L, Weiss R L, Borkovich K A, Dunlap J C (2006). A high-throughput gene knockout procedure for Neurospora reveals functions for multiple transcription factors. Proc Natl Acad Sci USA, 103(27): 10352–10357

28 da Fonseca P C, He J, Morris E P (2012). Molecular Model of the Human 26S Proteasome. Mol Cell, 46(1): 54–66

29 Dahlqvist J, Klar J, Tiwari N, Schuster J, Törmä H, Badhai J, Pujol R, van Steensel M A M, Brinkhuizen T, Gijezen L, Chaves A, Tadini G, Vahlquist A, Dahl N (2010). A single-nucleotide deletion in the POMP 5′ UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis. Am J Hum Genet, 86(4): 596–603

30 Dambacher C M, Worden E J, Herzik M A, Martin A, Lander G C (2016). Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition. eLife, 5: e13027

31 Dange T, Smith D, Noy T, Rommel P C, Jurzitza L, Cordero R J B, Legendre A, Finley D, Goldberg A L, Schmidt M (2011). Blm10 protein promotes proteasomal substrate turnover by an active gating mechanism. J Biol Chem, 286(50): 42830–42839

32 De M, Jayarapu K, Elenich L, Monaco J J, Colbert R A, Griffin T A (2003). Beta 2 subunit propeptides influence cooperative proteasome assembly. J Biol Chem, 278(8): 6153–6159

33 De La Mota-Peynado A, Lee S Y, Pierce B M, Wani P, Singh C R, Roelofs J (2013). The proteasome-associated protein Ecm29 inhibits proteasomal ATPase activity and in vivo protein degradation by the proteasome. J Biol Chem, 288(41): 29467–29481

34 DeMartino G N, Proske R J, Moomaw C R, Strong A A, Song X, Hisamatsu H, Tanaka K, Slaughter C A (1996). Identification, purification, and characterization of a PA700-dependent activator of the proteasome. J Biol Chem, 271(6): 3112–3118

35 Ding W X, Ni H M, Gao W, Yoshimori T, Stolz D B, Ron D, Yin X M (2007). Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol, 171(2): 513–524

36 Driscoll J, Brown M G, Finley D, Monaco J J (1993). MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature, 365(6443): 262–264

37 Enenkel C, Lehmann A, Kloetzel P M (1998). Subcellular distribution of proteasomes implicates a major location of protein degradation in the nuclear envelope-ER network in yeast. EMBO J, 17(21): 6144–6154

38 Estrin E, Lopez-Blanco J R, Chacon P, Martin A (2013). Formation of an Intricate Helical Bundle Dictates the Assembly of the 26S Proteasome Lid. Structure, 21(9): 1624–1635

39 Fehlker M, Wendler P, Lehmann A, Enenkel C (2003). Blm3 is part of nascent proteasomes and is involved in a late stage of nuclear proteasome assembly. EMBO Rep, 4(10): 959–963

40 Finley D (2009). Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem, 78(1): 477–513

41 Forouzan D, Ammelburg M, Hobel C F, Stroh L J, Sessler N, Martin J, Lupas A N (2012). The archaeal proteasome is regulated by a network of AAA ATPases. J Biol Chem, 287(46): 39254–39262

42 Forster A, Masters E I, Whitby F G, Robinson H, Hill C P (2005). The 1.9 A structure of a proteasome-11S activator complex and implications for proteasome-PAN/PA700 interactions. Mol Cell, 18(5): 589–599

43 Fort P, Kajava A V, Delsuc F, Coux O (2015). Evolution of proteasome regulators in eukaryotes. Genome Biol Evol, 7(5): 1363–1379

44 Frentzel S, Pesold-Hurt B, Seelig A, Kloetzel P M (1994). 20 S proteasomes are assembled via distinct precursor complexes. Processing of LMP2 and LMP7 proproteins takes place in 13–16 S preproteasome complexes. J Mol Biol, 236(4): 975–981

45 Fricke B, Heink S, Steffen J, Kloetzel P M, Kruger E (2007). The proteasome maturation protein POMP facilitates major steps of 20S proteasome formation at the endoplasmic reticulum. EMBO Rep, 8(12): 1170–1175

46 Fukunaga K, Kudo T, Toh-e A, Tanaka K, Saeki Y (2010). Dissection of the assembly pathway of the proteasome lid in Saccharomyces cerevisiae. Biochem Biophys Res Commun, 396(4): 1048–1053

47 Funakoshi M, Tomko R J Jr, Kobayashi H, Hochstrasser M (2009). Multiple assembly chaperones govern biogenesis of the proteasome regulatory particle base. Cell, 137(5): 887–899

48 Gaczynska M, Rock K L, Goldberg A L (1993). Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature, 365(6443): 264–267

49 Gerards W L, Enzlin J, Häner M, Hendriks I LA M, Aebi U , Bloemendal H, Boelens W (1997). The human alpha-type proteasomal subunit HsC8 forms a double ringlike structure, but does not assemble into proteasome-like particles with the beta-type subunits HsDelta or HsBPROS26. J Biol Chem, 272(15): 10080–10086

50 Gerards W L, de Jong W W, Bloemendal H, Boelens W (1998). The human proteasomal subunit HsC8 induces ring formation of other alpha-type subunits. J Mol Biol, 275(1): 113–121

51 Ghaemmaghami S, Huh W K, Bower K, Howson R W, Belle A, Dephoure N, O’Shea E K, Weissman J S (2003). Global analysis of protein expression in yeast. Nature, 425(6959): 737–741

52 Gille C, Goede A, Schlöetelburg C, Preißner R, Kloetzel P M, Göbel U B, Frömmel C (2003). A comprehensive view on proteasomal sequences: implications for the evolution of the proteasome. J Mol Biol, 326(5): 1437–1448

53 Gillette T G, Kumar B, Thompson D, Slaughter C A, DeMartino G N (2008). Differential roles of the COOH termini of AAA subunits of PA700 (19 S regulator) in asymmetric assembly and activation of the 26 S proteasome. J Biol Chem, 283(46): 31813–31822

54 Gomes A V (2013). Genetics of proteasome diseases. Scientifica (Cairo), 2013: 637629

55 Gragnoli C, Cronsell J (2007). PSMD9 gene variants within NIDDM2 may rarely contribute to type 2 diabetes. J Cell Physiol, 212(3): 568–571

56 Griffin T A, Nandi D, Cruz M, Fehling H J, Kaer L V, Monaco J J, Colbert R A (1998). Immunoproteasome assembly: cooperative incorporation of interferon gamma (IFN-gamma)-inducible subunits. J Exp Med, 187(1): 97–104

57 Griffin T A, Slack J P, McCluskey T S, Monaco J J, Colbert R A (2000). Identification of proteassemblin, a mammalian homologue of the yeast protein, Ump1p, that is required for normal proteasome assembly. Mol Cell Biol Res Commun, 3(4): 212–217

58 Groettrup M, Standera S, Stohwasser R, Kloetzel P M (1997). The subunits MECL-1 and LMP2 are mutually required for incorporation into the 20S proteasome. Proc Natl Acad Sci USA, 94(17): 8970–8975

59 Groll M, Brandstetter H, Bartunik H, Bourenkow G, Huber R (2003). Investigations on the maturation and regulation of archaebacterial proteasomes. J Mol Biol, 327(1): 75–83

60 Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik H D, Huber R (1997). Structure of 20S proteasome from yeast at 2.4 A resolution. Nature, 386(6624): 463–471

61 Groll M, Glickman M H, Finley D, Bajorek M, Köhler A, Moroder L, Rubin D M, Huber R (2000). A gated channel into the proteasome core particle. Nat Struct Biol, 7(11): 1062–1067

62 Groll M, Heinemeyer W, Jager S, Ullrich T, Bochtler M, Wolf D H, Huber R (1999). The catalytic sites of 20S proteasomes and their role in subunit maturation: a mutational and crystallographic study. Proc Natl Acad Sci USA, 96(20): 10976–10983

63 Haarer B, Aggeli D, Viggiano S, Burke D J, Amberg D C (2011). Novel interactions between actin and the proteasome revealed by complex haploinsufficiency. PLoS Genet, 7(9): e1002288

64 Hanssum A, Zhong Z, Rousseau A, Krzyzosiak A, Sigurdardottir A, Bertolotti A (2014). An inducible chaperone adapts proteasome assembly to stress. Mol Cell, 55(4): 566–577

65 Hatanaka A, Chen B, Sun J Q, Mano Y, Funakoshi M, Kobayashi H, Ju Y, Mizutani T, Shinmyozu K, Nakayama J, Miyamoto K, Uchida H, Oki M (2011). Fub1p, a novel protein isolated by boundary screening, binds the proteasome complex. Genes Genet Syst, 86(5): 305–314

66 Heinemeyer W, Fischer M, Krimmer T, Stachon U, Wolf D H (1997). The active sites of the eukaryotic 20 S proteasome and their involvement in subunit precursor processing. J Biol Chem, 272(40): 25200–25209

67 Heink S, Ludwig D, Kloetzel P M, Kruger E (2005). IFN-gamma-induced immune adaptation of the proteasome system is an accelerated and transient response. Proc Natl Acad Sci USA, 102(26): 9241–9246

68 Hirano Y, Hayashi H, Iemura S, Hendil K B, Niwa S, Kishimoto T, Kasahara M, Natsume T, Tanaka K, Murata S (2006). Cooperation of multiple chaperones required for the assembly of mammalian 20S proteasomes. Mol Cell, 24(6): 977–984

69 Hirano Y, Hendil K B, Yashiroda H, Iemura S, Nagane R, Hioki Y, Natsume T, Tanaka K, Murata S (2005). A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes. Nature, 437(7063): 1381–1385

70 Hirano Y, Kaneko T, Okamoto K, Bai M, Yashiroda H, Furuyama K, Kato K, Tanaka K, Murata S (2008). Dissecting beta-ring assembly pathway of the mammalian 20S proteasome. EMBO J, 27(16): 2204–2213

71 Hoang B, Benavides A, Shi Y, Frost P, Lichtenstein A (2009). Effect of autophagy on multiple myeloma cell viability. Mol Cancer Ther, 8(7): 1974–1984

72 Hoefer M M, Boneberg E M, Grotegut S, Kusch J, Illges H (2006). Possible tetramerisation of the proteasome maturation factor POMP/proteassemblin/hUmp1 and its subcellular localisation. Int J Biol Macromol, 38(3-5): 259–267

73 Huang X, Luan B, Wu J, Shi Y (2016). An atomic structure of the human 26S proteasome. Nat Struct Mol Biol, 23(9): 778–785

74 Huber E M, Heinemeyer W, Li X, Arendt C S, Hochstrasser M, Groll M (2016). A unified mechanism for proteolysis and autocatalytic activation in the 20S proteasome. Nat Commun, 7: 10900

75 Huh W K, Falvo J V, Gerke L C, Carroll A S, Howson R W, Weissman J S, O’Shea E K (2003). Global analysis of protein localization in budding yeast. Nature, 425(6959): 686–691

76 Ishii K, Noda M, Yagi H, Thammaporn R, Seetaha S, Satoh T, Kato K, Uchiyama S (2015). Disassembly of the self-assembled, double-ring structure of proteasome alpha7 homo-tetradecamer by alpha6. Sci Rep, 5: 18167

77 Isono E, Nishihara K, Saeki Y, Yashiroda H, Kamata N, Ge L, Ueda T, Kikuchi Y, Tanaka K, Nakano A, Toh-e A (2007). The assembly pathway of the 19S regulatory particle of the yeast 26S proteasome. Mol Biol Cell, 18(2): 569–580

78 Iwata A, Riley B E, Johnston J A, Kopito R R (2005). HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem, 280(48): 40282–40292

79 Jager S, Groll M, Huber R, Wolf D H, Heinemeyer W (1999). Proteasome beta-type subunits: unequal roles of propeptides in core particle maturation and a hierarchy of active site function. J Mol Biol, 291(4): 997–1013

80 Ju D, Xie Y (2004). Proteasomal degradation of RPN4 via two distinct mechanisms, ubiquitin-dependent and-independent. J Biol Chem, 279(23): 23851–23854

81 Kaganovich D, Kopito R, Frydman J (2008). Misfolded proteins partition between two distinct quality control compartments. Nature, 454(7208): 1088–1095

82 Kaneko T, Hamazaki J, Iemura S, Sasaki K, Furuyama K, Natsume T, Tanaka K, Murata S (2009). Assembly pathway of the Mammalian proteasome base subcomplex is mediated by multiple specific chaperones. Cell, 137(5): 914–925

83 Kim D U, Hayles J, Kim D, Wood V, Park H O, Won M, Yoo H S, Duhig T, Nam M, Palmer G, Han S, Jeffery L, Baek S T, Lee H, Shim Y S, Lee M, Kim L, Heo K S, Noh E J, Lee A R, Jang Y J, Chung K S, Choi S J, Park J Y, Park Y, Kim H M, Park S K, Park H J, Kang E J, Kim H B, Kang H S, Park H M, Kim K, Song K, Song K B, Nurse P, Hoe K L (2010a). Analysis of a genome-wide set of gene deletions in the fission yeast Schizosaccharomyces pombe. Nat Biotechnol, 28(6): 617–623

84 Kim S, Saeki Y, Fukunaga K, Suzuki A, Takagi K, Yamane T, Tanaka K, Mizushima T, Kato K (2010b). Crystal structure of yeast rpn14, a chaperone of the 19 S regulatory particle of the proteasome. J Biol Chem, 285(20): 15159–15166

85 Kim Y C, Snoberger A, Schupp J, Smith D M (2015). ATP binding to neighbouring subunits and intersubunit allosteric coupling underlie proteasomal ATPase function. Nat Commun, 6(8520):1

86 Kingsbury D J, Griffin T A, Colbert R A (2000). Novel propeptide function in 20 S proteasome assembly influences beta subunit composition. J Biol Chem, 275(31): 24156–24162

87 Kleijnen M F, Roelofs J, Park S, Hathaway N A, Glickman M, King R W, Finley D (2007). Stability of the proteasome can be regulated allosterically through engagement of its proteolytic active sites. Nat Struct Mol Biol, 14(12): 1180–1188

88 Kloetzel P M (2004). Generation of major histocompatibility complex class I antigens: functional interplay between proteasomes and TPPII. Nat Immunol, 5(7): 661–669

89 Kock M, Nunes M M, Hemann M, Kube S, Jürgen Dohmen R, Herzog F, Ramos P C, Wendler P (2015). Proteasome assembly from 15S precursors involves major conformational changes and recycling of the Pba1-Pba2 chaperone. Nat Commun, 6: 6123

90 Koizumi S, Irie T, Hirayama S, Sakurai Y, Yashiroda H, Naguro I, Ichijo H, Hamazaki J, Murata S (2016). The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction. eLife, 5: e18357

91 Kragelund B B, Schenstrom S M, Rebula C A, Panse V G, Hartmann-Petersen R (2016). DSS1/Sem1, a multifunctional and intrinsically disordered protein. Trends Biochem Sci, 41(5): 446–459

92 Kriegenburg F, Seeger M, Saeki Y, Tanaka K, Lauridsen A M B, Hartmann-Petersen R, Hendil K B (2008). Mammalian 26S proteasomes remain intact during protein degradation. Cell, 135(2): 355–365

93 Kulak N A, Pichler G, Paron I, Nagaraj N, Mann M (2014). Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells. Nat Methods, 11(3): 319–324

94 Kusmierczyk A R, Hochstrasser M (2008). Some assembly required: dedicated chaperones in eukaryotic proteasome biogenesis. Biol Chem, 389(9): 1143–1151

95 Kusmierczyk A R, Kunjappu M J, Funakoshi M, Hochstrasser M (2008). A multimeric assembly factor controls the formation of alternative 20S proteasomes. Nat Struct Mol Biol, 15(3): 237–244

96 Kusmierczyk A R, Kunjappu M J, Kim R Y, Hochstrasser M (2011). A conserved 20S proteasome assembly factor requires a C-terminal HbYX motif for proteasomal precursor binding. Nat Struct Mol Biol, 18(5): 622–629

97 Kwon Y D, Nagy I, Adams P D, Baumeister W, Jap B K (2004a). Crystal structures of the Rhodococcus proteasome with and without its pro-peptides: implications for the role of the pro-peptide in proteasome assembly. J Mol Biol, 335(1): 233–245

98 Kwon Y D, Nagy I, Adams P D, Baumeister W, Jap B K (2004b). Crystal structures of the Rhodococcus proteasome with and without its pro-peptides: implications for the role of the pro-peptide in proteasome assembly. J Mol Biol, 335(1): 233–245

99 Lander G C, Estrin E, Matyskiela M E, Bashore C, Nogales E, Martin A (2012). Complete subunit architecture of the proteasome regulatory particle. Nature, 482: 186–191

100 Lasker K, Forster F, Bohn S, Walzthoeni T, Villa E, Unverdorben P, Beck F, Aebersold R, Sali A, Baumeister W (2012). Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach. Proc Natl Acad Sci USA, 109(5): 1380–1387

101 Le Tallec B, Barrault M B, Courbeyrette R, Guerois R, Marsolier-Kergoat M C, Peyroche A (2007). 20S proteasome assembly is orchestrated by two distinct pairs of chaperones in yeast and in mammals. Mol Cell, 27(4): 660–674

102 Le Tallec B, Barrault M B, Guerois R, Carre T, Peyroche A (2009). Hsm3/S5b participates in the assembly pathway of the 19S regulatory particle of the proteasome. Mol Cell, 33(3): 389–399

103 Lee S C, Shaw B D (2007). A novel interaction between N-myristoylation and the 26S proteasome during cell morphogenesis. Mol Microbiol, 63(4): 1039–1053

104 Lee S Y, De la Mota-Peynado A, Roelofs J (2011). Loss of Rpt5 protein interactions with the core particle and Nas2 protein causes the formation of faulty proteasomes that are inhibited by Ecm29 protein. J Biol Chem, 286(42): 36641–36651

105 Leggett D S, Hanna J, Borodovsky A, Crosas B, Schmidt M, Baker R T, Walz T, Ploegh H, Finley D (2002). Multiple associated proteins regulate proteasome structure and function. Mol Cell, 10(3): 495–507

106 Lehmann A, Janek K, Braun B, Kloetzel P M, Enenkel C (2002). 20 S proteasomes are imported as precursor complexes into the nucleus of yeast. J Mol Biol, 317(3): 401–413

107 Lehmann A, Niewienda A, Jechow K, Janek K, Enenkel C (2010). Ecm29 fulfils quality control functions in proteasome assembly. Mol Cell, 38(6): 879–888

108 Lehrbach N J, Ruvkun G (2016). Proteasome dysfunction triggers activation of SKN-1A/Nrf1 by the aspartic protease DDI-1. eLife, 5: e17721

109 Lek M, Karczewski K J, Minikel E V, Samocha K E, Banks E, Fennell T, O’Donnell-Luria A H, Ware J S, Hill A J, Cummings B B, Tukiainen T, Birnbaum D P, Kosmicki J A, Duncan L E, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper D N, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki M I, Moonshine A L, Natarajan P, Orozco L, Peloso G M, Poplin R, Rivas M A, Ruano-Rubio V, Rose S A, Ruderfer D M, Shakir K, Stenson P D, Stevens C, Thomas B P, Tiao G, Tusie-Luna M T, Weisburd B, Won H H, Yu D, Altshuler D M, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez J C, Gabriel S B, Getz G, Glatt S J, Hultman C M, Kathiresan S, Laakso M, McCarroll S, McCarthy M I, McGovern D, McPherson R, Neale B M, Palotie A, Purcell S M, Saleheen D, Scharf J M, Sklar P, Sullivan P F, Tuomilehto J, Tsuang M T, Watkins H C, Wilson J G, Daly M J, MacArthur D G (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature, 536(7616): 285–291

110 Li D, Dong Q, Tao Q, Gu J, Cui Y, Jiang X, Yuan J, Li W, Xu R, Jin Y, Li P, Weaver D T, Ma Q, Liu X, Cao C (2015). c-Abl regulates proteasome abundance by controlling the ubiquitin-proteasomal degradation of PSMA7 subunit. Cell Reports, 10(4): 484–496

111 Li J, Zou C, Bai Y, Wazer D E, Band V, Gao Q (2006). DSS1 is required for the stability of BRCA2. Oncogene, 25(8): 1186–1194

112 Li X, Kusmierczyk A R, Wong P, Emili A, Hochstrasser M (2007). beta-Subunit appendages promote 20S proteasome assembly by overcoming an Ump1-dependent checkpoint. EMBO J, 26(9): 2339–2349

113 Li X, Li Y, Arendt C S, Hochstrasser M (2016). Distinct elements in the proteasomal beta5 subunit propeptide required for autocatalytic processing and proteasome assembly. J Biol Chem, 291(4): 1991–2003

114 Li X, Thompson D, Kumar B, DeMartino G N (2014). Molecular and cellular roles of PI31 (PSMF1) protein in regulation of proteasome function. J Biol Chem, 289(25): 17392–17405

115 Liu J, Yuan X, Liu J, Tian L, Quan J, Liu J, Chen X, Wang Y, Shi Z, Zhang J (2012). Validation of the association between PSMA6 -8 C/G polymorphism and type 2 diabetes mellitus in Chinese Dongxiang and Han populations. Diabetes Res Clin Pract, 98(2): 295–301

116 Lowe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R (1995). Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution. Science, 268(5210): 533–539

117 Luan B, Huang X, Wu J, Mei Z, Wang Y, Xue X, Yan C, Wang J, Finley D J, Shi Y, Wang F (2016). Structure of an endogenous yeast 26S proteasome reveals two major conformational states. Proc Natl Acad Sci USA, 113(10): 2642–2647

118 Mannhaupt G, Schnall R, Karpov V, Vetter I, Feldmann H (1999). Rpn4p acts as a transcription factor by binding to PACE, a nonamer box found upstream of 26S proteasomal and other genes in yeast. FEBS Lett, 450(1-2): 27–34

119 Mao I, Liu J, Li X, Luo H (2008). REGgamma, a proteasome activator and beyond? Cellular and molecular life sciences. Cell Mol Life Sci, 65: 3971–3980

120 Marques A J, Glanemann C, Ramos P C, Dohmen R J (2007). The C-terminal extension of the beta7 subunit and activator complexes stabilize nascent 20 S proteasomes and promote their maturation. J Biol Chem, 282(48): 34869–34876

121 Marshall R S, Li F, Gemperline D C, Book A J, Vierstra R D (2015). Autophagic degradation of the 26S proteasome is mediated by the dual ATG8/ubiquitin receptor RPN10 in Arabidopsis. Mol Cell, 58(6): 1053–1066

122 Marshall R S, McLoughlin F, Vierstra R D (2016). Autophagic turnover of inactive 26S Proteasomes in yeast is directed by the ubiquitin receptor Cue5 and the Hsp42 chaperone. Cell Reports, 16(6): 1717–1732

123 Matyskiela M E, Lander G C, Martin A (2013). Conformational switching of the 26S proteasome enables substrate degradation. Nat Struct Mol Biol, 20(7): 781–788

124 Mayr J, Seemuller E, Muller S A, Engel A, Baumeister W (1998a). Late events in the assembly of 20S proteasomes. J Struct Biol, 124(2-3): 179–188

125 Mayr J, Seemuller E, Muller S A, Engel A, Baumeister W (1998b). Late events in the assembly of 20S proteasomes. J Struct Biol, 124(2-3): 179–188

126 Mayr J, Wang H R, Nederlof P, Baumeister W (1999). The import pathway of human and Thermoplasma 20S proteasomes into HeLa cell nuclei is different from that of classical NLS-bearing proteins. Biol Chem, 380(10): 1183–1192

127 Meiners S, Heyken D, Weller A, Ludwig A, Stangl K, Kloetzel P M, Kruger E (2003). Inhibition of proteasome activity induces concerted expression of proteasome genes and de novo formation of Mammalian proteasomes. J Biol Chem, 278(24): 21517–21525

128 Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y, Tanaka K (2007). Regulation of CD8⁺ T cell development by thymus-specific proteasomes. Science, 316(5829): 1349–1353

129 Nakamura Y, Umehara T, Tanaka A, Horikoshi M, Padmanabhan B, Yokoyama S (2007). Structural basis for the recognition between the regulatory particles Nas6 and Rpt3 of the yeast 26S proteasome. Biochem Biophys Res Commun, 359(3): 503–509

130 Nandi D, Woodward E, Ginsburg D B, Monaco J J (1997). Intermediates in the formation of mouse 20S proteasomes: implications for the assembly of precursor beta subunits. EMBO J, 16(17): 5363–5375

131 Nederlof P M, Wang H R, Baumeister W (1995). Nuclear localization signals of human and Thermoplasma proteasomal alpha subunits are functional in vitro. Proc Natl Acad Sci USA, 92(26): 12060–12064

132 Pack C G, Yukii H, Toh-e A, Kudo T, Tsuchiya H, Kaiho A, Sakata E, Murata S, Yokosawa H, Sako Y, Baumeister W, Tanaka K, Saeki Y (2014). Quantitative live-cell imaging reveals spatio-temporal dynamics and cytoplasmic assembly of the 26S proteasome. Nat Commun, 5: 3396

133 Padmanabhan A, Vuong S A, Hochstrasser M (2016). Assembly of an evolutionarily conserved alternative proteasome isoform in human cells. Cell Reports, 14(12): 2962–2974

134 Pandey U B, Nie Z, Batlevi Y, McCray B A, Ritson G P, Nedelsky N B, Schwartz S L, DiProspero N A, Knight M A, Schuldiner O, Padmanabhan R, Hild M, Berry D L, Garza D, Hubbert C C, Yao T P, Baehrecke E H, Taylor J P (2007). HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature, 447(7146): 859–863

135 Panfair D, Ramamurthy A, Kusmierczyk A R (2015). Alpha-ring independent assembly of the 20S proteasome. Sci Rep, 5: 13130

136 Paraskevopoulos K, Kriegenburg F, Tatham M H, Rösner H I, Medina B, Larsen I B, Brandstrup R, Hardwick K G, Hay R T, Kragelund B B, Hartmann-Petersen R, Gordon C (2014). Dss1 is a 26S proteasome ubiquitin receptor. Mol Cell, 56(3): 453–461

137 Park S, Kim W, Tian G, Gygi S P, Finley D (2011). Structural defects in the regulatory particle-core particle interface of the proteasome induce a novel proteasome stress response. J Biol Chem, 286(42): 36652–36666

138 Park S, Li X, Kim H M, Singh C R, Tian G, Hoyt M A, Lovell S, Battaile K P, Zolkiewski M, Coffino P, Roelofs J, Cheng Y, Finley D (2013). Reconfiguration of the proteasome during chaperone-mediated assembly. Nature, 497(7450): 512–516

139 Park S, Roelofs J, Kim W, Robert J, Schmidt M, Gygi S P, Finley D (2009). Hexameric assembly of the proteasomal ATPases is templated through their C termini. Nature, 459(7248): 866–870

140 Pathare G R, Nagy I, Sledz P, Anderson D J, Zhou H J, Pardon E, Steyaert J, Forster F, Bracher A, Baumeister W (2014). Crystal structure of the proteasomal deubiquitylation module Rpn8-Rpn11. Proc Natl Acad Sci USA, 111(8): 2984–2989

141 Peters L Z, Karmon O, David-Kadoch G, Hazan R, Yu T, Glickman M H, Ben-Aroya S (2015). The protein quality control machinery regulates its misassembled proteasome subunits. PLoS Genet, 11(4): e1005178

142 Radhakrishnan S K, den Besten W, Deshaies R J (2014). p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition. eLife, 3: e01856

143 Radhakrishnan S K, Lee C S, Young P, Beskow A, Chan J Y, Deshaies R J (2010). Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell, 38(1): 17–28

144 Ramos P C, Hockendorff J, Johnson E S, Varshavsky A, Dohmen R J (1998). Ump1p is required for proper maturation of the 20S proteasome and becomes its substrate upon completion of the assembly. Cell, 92(4): 489–499

145 Ramos P C, Marques A J, London M K, Dohmen R J (2004). Role of C-terminal extensions of subunits beta2 and beta7 in assembly and activity of eukaryotic proteasomes. J Biol Chem, 279(14): 14323–14330

146 Reits E A, Benham A M, Plougastel B, Neefjes J, Trowsdale J (1997). Dynamics of proteasome distribution in living cells. EMBO J, 16(20): 6087–6094

147 Roelofs J, Park S, Haas W, Tian G, McAllister F E, Huo Y, Lee B H, Zhang F, Shi Y, Gygi S P, Finley D (2009). Chaperone-mediated pathway of proteasome regulatory particle assembly. Nature, 459(7248): 861–865

148 Russell S J, Steger K A, Johnston S A (1999). Subcellular localization, stoichiometry, and protein levels of 26 S proteasome subunits in yeast. J Biol Chem, 274(31): 21943–21952

149 Sa-Moura B, Simões A M, Fraga J, Fernandes H, Abreu I A, Botelho H M, Gomes C M, Marques A J, Dohmen R J, Ramos P C, Macedo-Ribeiro S (2013). Biochemical and biophysical characterization of recombinant yeast proteasome maturation factor ump1. Comput Struct Biotechnol J, 7(8): e201304006

150 Sadre-Bazzaz K, Whitby F G, Robinson H, Formosa T, Hill C P (2010). Structure of a Blm10 complex reveals common mechanisms for proteasome binding and gate opening. Mol Cell, 37(5): 728–735

151 Saeki Y, Toh E A, Kudo T, Kawamura H, Tanaka K (2009). Multiple proteasome-interacting proteins assist the assembly of the yeast 19S regulatory particle. Cell, 137(5): 900–913

152 Sakata E, Stengel F, Fukunaga K, Zhou M, Saeki Y, Förster F, Baumeister W, Tanaka K, Robinson C V (2011). The catalytic activity of Ubp6 enhances maturation of the proteasomal regulatory particle. Mol Cell, 42(5): 637–649

153 Satoh T, Saeki Y, Hiromoto T, Wang Y H, Uekusa Y, Yagi H, Yoshihara H, Yagi-Utsumi M, Mizushima T, Tanaka K, Kato K (2014). Structural basis for proteasome formation controlled by an assembly chaperone nas2. Structure, 22(5): 731–743

154 Savulescu A F, Shorer H, Kleifeld O, Cohen I, Gruber R, Glickman M H, Harel A (2011). Nuclear import of an intact preassembled proteasome particle. Mol Biol Cell, 22(6): 880–891

155 Schmidt M, Haas W, Crosas B, Santamaria P G, Gygi S P, Walz T, Finley D (2005). The HEAT repeat protein Blm10 regulates the yeast proteasome by capping the core particle. Nat Struct Mol Biol, 12(4): 294–303

156 Schmidtke G, Kraft R, Kostka S, Henklein P, Frömmel C, Löwe J, Huber R, Kloetzel P M, Schmidt M (1996). Analysis of mammalian 20S proteasome biogenesis: the maturation of beta-subunits is an ordered two-step mechanism involving autocatalysis. EMBO J, 15: 6887–6898

157 Schmidtke G, Schmidt M, Kloetzel P M (1997). Maturation of mammalian 20 S proteasome: purification and characterization of 13 S and 16 S proteasome precursor complexes. J Mol Biol, 268(1): 95–106

158 Schweitzer A, Aufderheide A, Rudack T, Beck F, Pfeifer G, Plitzko J M, Sakata E, Schulten K, Förster F, Baumeister W (2016). Structure of the human 26S proteasome at a resolution of 3.9 A. Proc Natl Acad Sci USA, 113(28): 7816–7821

159 Sha Z, Goldberg A L (2014). Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97. Curr Biol, 24(14): 1573–1583

160 Sharon M, Taverner T, Ambroggio X I, Deshaies R J, Robinson C V (2006). Structural organization of the 19S proteasome lid: insights from MS of intact complexes. PLoS Biol, 4(8): e267

161 Sharon M, Witt S, Glasmacher E, Baumeister W, Robinson C V (2007). Mass spectrometry reveals the missing links in the assembly pathway of the bacterial 20 S proteasome. J Biol Chem, 282(25): 18448–18457

162 Shi Y, Chen X, Elsasser S, Stocks B B, Tian G, Lee B H, Shi Y, Zhang N, de Poot S A H, Tuebing F, Sun S, Vannoy J, Tarasov S G, Engen J R, Finley D, Walters K J (2016). Rpn1 provides adjacent receptor sites for substrate binding and deubiquitination by the proteasome. Science

163 Shirozu R, Yashiroda H, Murata S (2015). Identification of minimum Rpn4-responsive elements in genes related to proteasome functions. FEBS Lett, 589(8): 933–940

164 Singh C R, Lovell S, Mehzabeen N, Chowdhury W Q, Geanes E S, Battaile K P, Roelofs J (2014). 1.15 A resolution structure of the proteasome-assembly chaperone Nas2 PDZ domain. Acta Crystallogr F Struct Biol Commun, 70(4): 418–423

165 Sledz P, Unverdorben P, Beck F, Pfeifer G, Schweitzer A, Forster F, Baumeister W (2013). Structure of the 26S proteasome with ATP-gammaS bound provides insights into the mechanism of nucleotide-dependent substrate translocation. Proc Natl Acad Sci USA, 110(18): 7264–7269

166 Smith D M, Chang S C, Park S, Finley D, Cheng Y, Goldberg A L (2007). Docking of the proteasomal ATPases’ carboxyl termini in the 20S proteasome’s alpha ring opens the gate for substrate entry. Mol Cell, 27(5): 731–744

167 Sokolova V, Li F, Polovin G, Park S (2015). Proteasome activation is mediated via a functional switch of the Rpt6 C-terminal tail following chaperone-dependent assembly. Sci Rep, 5: 14909

168 Stadtmueller B M, Hill C P (2011). Proteasome activators. Mol Cell, 41(1): 8–19

169 Stadtmueller B M, Kish-Trier E, Ferrell K, Petersen C N, Robinson H, Myszka D G, Eckert D M, Formosa T, Hill C P (2012). Structure of a proteasome Pba1-Pba2 complex: implications for proteasome assembly, activation, and biological function. J Biol Chem, 287(44): 37371–37382

170 Takagi K, Kim S, Yukii H, Ueno M, Morishita R, Endo Y, Kato K, Tanaka K, Saeki Y, Mizushima T (2012). Structural basis for specific recognition of Rpt1p, an ATPase subunit of 26S proteasome, by proteasome-dedicated chaperone Hsm3p. J Biol Chem, 287(15): 12172–12182

171 Takagi K, Saeki Y, Yashiroda H, Yagi H, Kaiho A, Murata S, Yamane T, Tanaka K, Mizushima T, Kato K (2014). Pba3-Pba4 heterodimer acts as a molecular matchmaker in proteasome alpha-ring formation. Biochem Biophys Res Commun, 450(2): 1110–1114

172 Takeuchi J, Tamura T (2004). Recombinant ATPases of the yeast 26S proteasome activate protein degradation by the 20S proteasome. FEBS Lett, 565(1-3): 39–42

173 Tanaka K, Yoshimura T, Tamura T, Fujiwara T, Kumatori A, Ichihara A (1990). Possible mechanism of nuclear translocation of proteasomes. FEBS Lett, 271(1-2): 41–46

174 Thompson D, Hakala K, DeMartino G N (2009). Subcomplexes of PA700, the 19S regulator of the 26 S proteasome, reveal relative roles of AAA subunits in 26 S proteasome assembly and activation and ATPase activity. J Biol Chem, 284(37): 24891–24903

175 Tian G, Park S, Lee M J, Huck B, McAllister F, Hill C P, Gygi S P, Finley D (2011). An asymmetric interface between the regulatory and core particles of the proteasome. Nat Struct Mol Biol, 18(11): 1259–1267

176 Tomko R J Jr, Funakoshi M, Schneider K, Wang J, Hochstrasser M (2010). Heterohexameric ring arrangement of the eukaryotic proteasomal ATPases: implications for proteasome structure and assembly. Mol Cell, 38(3): 393–403

177 Tomko R J Jr, Hochstrasser M (2011). Incorporation of the Rpn12 subunit couples completion of proteasome regulatory particle lid assembly to lid-base joining. Mol Cell, 44(6): 907–917

178 Tomko R J Jr, Hochstrasser M (2013). Molecular architecture and assembly of the eukaryotic proteasome. Annu Rev Biochem, 82(1): 415–445

179 Tomko R J Jr, Hochstrasser M (2014). The intrinsically disordered Sem1 protein functions as a molecular tether during proteasome lid biogenesis. Mol Cell, 53(3): 433–443

180 Tomko R J Jr, Taylor D W, Chen Z A, Wang H W, Rappsilber J, Hochstrasser M (2015). A Single alpha helix drives extensive remodeling of the proteasome lid and completion of regulatory particle assembly. Cell, 163(2): 432–444

181 Uekusa Y, Okawa K, Yagi-Utsumi M, Serve O, Nakagawa Y, Mizushima T, Yagi H, Saeki Y, Tanaka K, Kato K (2014). Backbone (1)H, (1)(3)C and (1)(5)N assignments of yeast Ump1, an intrinsically disordered protein that functions as a proteasome assembly chaperone. Biomol NMR Assign, 8(2): 383–386

182 Unno M, Mizushima T, Morimoto Y, Tomisugi Y, Tanaka K, Yasuoka N, Tsukihara T (2002). The structure of the mammalian 20S proteasome at 2.75 A resolution. Structure, 10(5): 609–618

183 Unverdorben P, Beck F, led P, Schweitzer A, Pfeifer G, Plitzko J M, Baumeister W, Forster F (2014). Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome. Proc Natl Acad Sci USA, 111(15): 5544–5549

184 Ustrell V, Hoffman L, Pratt G, Rechsteiner M (2002). PA200, a nuclear proteasome activator involved in DNA repair. EMBO J, 21(13): 3516–3525

185 Velichutina I, Connerly P L, Arendt C S, Li X, Hochstrasser M (2004). Plasticity in eucaryotic 20S proteasome ring assembly revealed by a subunit deletion in yeast. EMBO J, 23(3): 500–510

186 Verma R, (2002). Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science, 298(5593): 611–615

187 Volker C, Lupas A N (2002). Molecular evolution of proteasomes. Curr Top Microbiol Immunol, 268: 1–22

188 Waite K A, De-La Mota-Peynado A, Vontz G, Roelofs J (2016). Starvation induces proteasome autophagy with different pathways for core and regulatory particles. J Biol Chem, 291(7): 3239–3253

189 Wang H R, Kania M, Baumeister W, Nederlof P M (1997). Import of human and Thermoplasma 20S proteasomes into nuclei of HeLa cells requires functional NLS sequences. Eur J Cell Biol, 73: 105–113

190 Wang W, Chan J Y (2006). Nrf1 is targeted to the endoplasmic reticulum membrane by an N-terminal transmembrane domain. Inhibition of nuclear translocation and transacting function. J Biol Chem, 281(28): 19676–19687

191 Wani P S, Rowland M A, Ondracek A, Deeds E J, Roelofs J (2015). Maturation of the proteasome core particle induces an affinity switch that controls regulatory particle association. Nat Commun, 6: 6384

192 Wani P S, Suppahia A, Capalla X, Ondracek A, Roelofs J (2016). Phosphorylation of the C-terminal tail of proteasome subunit alpha7 is required for binding of the proteasome quality control factor Ecm29. Sci Rep, 6: 27873

193 Weberruss M H, Savulescu A F, Jando J, Bissinger T, Harel A, Glickman M H, Enenkel C (2013). Blm10 facilitates nuclear import of proteasome core particles. EMBO J, 32(20): 2697–2707

194 Wei S J, Williams J G, Dang H, Darden T A, Betz B L, Humble M M, Chang F M, Trempus C S, Johnson K, Cannon R E, Tennant R W (2008). Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation. J Mol Biol, 383(3): 693–712

195 Welk V, Coux O, Kleene V, Abeza C, Trümbach D, Eickelberg O, Meiners S (2016). Inhibition of proteasome activity induces formation of alternative proteasome complexes. J Biol Chem, 291(25): 13147–13159

196 Wendler P, Lehmann A, Janek K, Baumgart S, Enenkel C (2004). The bipartite nuclear localization sequence of Rpn2 is required for nuclear import of proteasomal base complexes via karyopherin alphabeta and proteasome functions. J Biol Chem, 279(36): 37751–37762

197 Whitby F G, Masters E I, Kramer L, Knowlton J R, Yao Y, Wang C C, Hill C P (2000). Structural basis for the activation of 20S proteasomes by 11S regulators. Nature, 408(6808): 115–120

198 Witt E, Zantopf D, Schmidt M, Kraft R, Kloetzel P M, Kruger E (2000). Characterisation of the newly identified human Ump1 homologue POMP and analysis of LMP7(beta 5i) incorporation into 20 S proteasomes. J Mol Biol, 301(1): 1–9

199 Wollenberg K, Swaffield J C (2001). Evolution of proteasomal ATPases. Mol Biol Evol, 18(6): 962–974

200 Worden E J, Padovani C, Martin A (2014). Structure of the Rpn11-Rpn8 dimer reveals mechanisms of substrate deubiquitination during proteasomal degradation. Nat Struct Mol Biol, 21(3): 220–227

201 Xie Y, Varshavsky A (2001). RPN4 is a ligand, substrate, and transcriptional regulator of the 26S proteasome: a negative feedback circuit. Proc Natl Acad Sci USA, 98(6): 3056–3061

202 Yao T, Cohen R E (2002). A cryptic protease couples deubiquitination and degradation by the proteasome. Nature, 419(6905): 403–407

203 Yao Y, Toth C R, Huang L, Wong M L, Dias P, Burlingame A L, Coffino P, Wang C C (1999). alpha5 subunit in Trypanosoma brucei proteasome can self-assemble to form a cylinder of four stacked heptamer rings. Biochem J, 344(Pt 2): 349–358

204 Yashiroda H, Mizushima T, Okamoto K, Kameyama T, Hayashi H, Kishimoto T, Niwa S, Kasahara M, Kurimoto E, Sakata E, Takagi K, Suzuki A, Hirano Y, Murata S, Kato K, Yamane T, Tanaka K (2008). Crystal structure of a chaperone complex that contributes to the assembly of yeast 20S proteasomes. Nat Struct Mol Biol, 15(3): 228–236

205 Yashiroda H, Toda Y, Otsu S, Takagi K, Mizushima T, Murata S (2015). N-terminal alpha7 deletion of the proteasome 20S core particle substitutes for yeast PI31 function. Mol Cell Biol, 35(1): 141–152

206 Yu Y, Smith D M, Kim H M, Rodriguez V, Goldberg A L, Cheng Y (2010). Interactions of PAN’s C-termini with archaeal 20S proteasome and implications for the eukaryotic proteasome-ATPase interactions. EMBO J, 29(3): 692–702

207 Yu Z, Livnat-Levanon N, Kleifeld O, Mansour W, Nakasone M A, Castaneda C A, Dixon E K, Fushman D, Reis N, Pick E, Glickman M H (2015). Base-CP proteasome can serve as a platform for stepwise lid formation. Biosci Rep, 35(3): e00194

208 Zaiss D M, Standera S, Kloetzel P M, Sijts A J (2002). PI31 is a modulator of proteasome formation and antigen processing. Proc Natl Acad Sci USA, 99(22): 14344–14349

209 Zhang F, Hu M, Tian G, Zhang P, Finley D, Jeffrey P D, Shi Y (2009). Structural insights into the regulatory particle of the proteasome from Methanocaldococcus jannaschii. Mol Cell, 34(4): 473–484

210 Zhang Y, Lucocq J M, Yamamoto M, Hayes J D (2007). The NHB1 (N-terminal homology box 1) sequence in transcription factor Nrf1 is required to anchor it to the endoplasmic reticulum and also to enable its asparagine-glycosylation. Biochem J, 408(2): 161–172

211 Zhu K, Dunner K Jr, McConkey D J (2010). Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene, 29(3): 451–462

212 Zuhl F, Seemuller E, Golbik R, Baumeister W (1997). Dissecting the assembly pathway of the 20S proteasome. FEBS Lett, 418(1-2): 189–194

213 Zwickl P, Kleinz J, Baumeister W (1994). Critical elements in proteasome assembly. Nat Struct Biol, 1(11): 765–770

214 Zwickl P, Ng D, Woo K M, Klenk H P, Goldberg A L (1999). An archaebacterial ATPase, homologous to ATPases in the eukaryotic 26S proteasome, activates protein breakdown by 20 S proteasomes. J Biol Chem, 274(37): 26008–26014