Journal articles: '19S regulatory particle'

1

Ehlinger, Aaron, and Kylie J. Walters. "Structural Insights into Proteasome Activation by the 19S Regulatory Particle." Biochemistry 52, no. 21 (May 14, 2013): 3618–28. http://dx.doi.org/10.1021/bi400417a.

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Lim, Hyun-Suk, Chase T. Archer, and Thomas Kodadek. "Identification of a Peptoid Inhibitor of the Proteasome 19S Regulatory Particle." Journal of the American Chemical Society 129, no. 25 (June 2007): 7750–51. http://dx.doi.org/10.1021/ja072027p.

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Rosenzweig, Rina, Pawel A. Osmulski, Maria Gaczynska, and Michael H. Glickman. "The central unit within the 19S regulatory particle of the proteasome." Nature Structural & Molecular Biology 15, no. 6 (May 30, 2008): 573–80. http://dx.doi.org/10.1038/nsmb.1427.

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Greer, Susanna, Nagini Maganti, Meghna Thakkar, and Agnieszka Truax. "19S ATPase subunits of the 26S proteasome play critical roles in transcription elongation. (167.7)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 167.7. http://dx.doi.org/10.4049/jimmunol.188.supp.167.7.

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Abstract Major histocompatibility class II molecules are cell surface glycoproteins that present extracellular peptides to CD4+ T cells and initiate adaptive immune responses. MHC II molecules are inducibly expressed in response to interferon gamma and are tightly regulated at the level of transcription by a master regulator, the class II transactivator, CIITA. We have recently shown that the 26S proteasome, itself a master regulator of proteins, regulates transcription initiation at interferon gamma inducible CIITApIV and MHC II genes in a degradation independent manner. The 26S proteasome consists of two major subunits, a 19S regulatory particle and a 20S proteolytic core. The 19S contains six ATPases which associate with MHC II and CIITA promoters and play important roles in transcription initiation by recruiting critical histone modifying enzymes. To determine if the 19S ATPases function in transcription elongation, 19S ATPase binding and activity in CIITApIV coding regions was analyzed. ChIP assays indicate significant binding of 19S ATPases in CIITA coding regions, and knockdown of 19S ATPases results in significant decreases in RNA pol II binding throughout CIITApIV coding regions. Further, knockdown of 19S ATPases has minimal impact on the expression of short CIITApIV transcripts but significant negative impact on long transcript expression, indicating roles for 19S ATPases in RNA pol II processivity at CIITApIV and likely other inducible mammalian genes.

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Mendes, Marta L., and Gunnar Dittmar. "Analysis of the Dynamic Proteasome Structure by Cross-Linking Mass Spectrometry." Biomolecules 11, no. 4 (March 27, 2021): 505. http://dx.doi.org/10.3390/biom11040505.

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The 26S proteasome is a macromolecular complex that degrades proteins maintaining cell homeostasis; thus, determining its structure is a priority to understand its function. Although the 20S proteasome’s structure has been known for some years, the highly dynamic nature of the 19S regulatory particle has presented a challenge to structural biologists. Advances in cryo-electron microscopy (cryo-EM) made it possible to determine the structure of the 19S regulatory particle and showed at least seven different conformational states of the proteasome. However, there are still many questions to be answered. Cross-linking mass spectrometry (CLMS) is now routinely used in integrative structural biology studies, and it promises to take integrative structural biology to the next level, answering some of these questions.

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Shibahara, Tadashi, Hiroshi Kawasaki, and Hisashi Hirano. "Identification of the 19S regulatory particle subunits from the rice 26S proteasome." European Journal of Biochemistry 269, no. 5 (March 1, 2002): 1474–83. http://dx.doi.org/10.1046/j.1432-1033.2002.02792.x.

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Stanhill, Ariel, Cole M. Haynes, Yuhong Zhang, Guangwei Min, Matthew C. Steele, Juliya Kalinina, Enid Martinez, Cecile M. Pickart, Xiang-Peng Kong, and David Ron. "An Arsenite-Inducible 19S Regulatory Particle-Associated Protein Adapts Proteasomes to Proteotoxicity." Molecular Cell 23, no. 6 (September 2006): 875–85. http://dx.doi.org/10.1016/j.molcel.2006.07.023.

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Isono, Erika, Kiyoshi Nishihara, Yasushi Saeki, Hideki Yashiroda, Naoko Kamata, Liying Ge, Takashi Ueda, et al. "The Assembly Pathway of the 19S Regulatory Particle of the Yeast 26S Proteasome." Molecular Biology of the Cell 18, no. 2 (February 2007): 569–80. http://dx.doi.org/10.1091/mbc.e06-07-0635.

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The 26S proteasome consists of the 20S proteasome (core particle) and the 19S regulatory particle made of the base and lid substructures, and it is mainly localized in the nucleus in yeast. To examine how and where this huge enzyme complex is assembled, we performed biochemical and microscopic characterization of proteasomes produced in two lid mutants, rpn5-1 and rpn7-3, and a base mutant ΔN rpn2, of the yeast Saccharomyces cerevisiae. We found that, although lid formation was abolished in rpn5-1 mutant cells at the restrictive temperature, an apparently intact base was produced and localized in the nucleus. In contrast, in ΔN rpn2 cells, a free lid was formed and localized in the nucleus even at the restrictive temperature. These results indicate that the modules of the 26S proteasome, namely, the core particle, base, and lid, can be formed and imported into the nucleus independently of each other. Based on these observations, we propose a model for the assembly process of the yeast 26S proteasome.

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Oliveri, Franziska, Steffen Johannes Keller, Heike Goebel, Gerardo Omar Alvarez Salinas, and Michael Basler. "The ubiquitin-like modifier FAT10 is degraded by the 20S proteasome in vitro but not in cellulo." Life Science Alliance 6, no. 6 (April 3, 2023): e202201760. http://dx.doi.org/10.26508/lsa.202201760.

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Ubiquitin-independent protein degradation via the 20S proteasome without the 19S regulatory particle has gained increasing attention over the last years. The degradation of the ubiquitin-like modifier FAT10 by the 20S proteasome was investigated in this study. We found that FAT10 was rapidly degraded by purified 20S proteasomes in vitro, which was attributed to the weak folding of FAT10 and the N-terminally disordered tail. To confirm our results in cellulo, we established an inducible RNA interference system in which the AAA-ATPase Rpt2 of the 19S regulatory particle is knocked down to impair the function of the 26S proteasome. Using this system, degradation of FAT10 in cellulo was strongly dependent on functional 26S proteasome. Our data indicate that in vitro degradation studies with purified proteins do not necessarily reflect biological degradation mechanisms occurring in cells and, therefore, cautious data interpretation is required when 20S proteasome function is studied in vitro.

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Brockmann, Florian, Nicola Catone, Christine Wünsch, Fabian Offensperger, Martin Scheffner, Gunter Schmidtke, and Annette Aichem. "FAT10 and NUB1L cooperate to activate the 26S proteasome." Life Science Alliance 6, no. 8 (May 15, 2023): e202201463. http://dx.doi.org/10.26508/lsa.202201463.

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The interaction of the 19S regulatory particle of the 26S proteasome with ubiquitylated proteins leads to gate opening of the 20S core particle and increases its proteolytic activity by binding of the ubiquitin chain to the inhibitory deubiquitylation enzyme USP14 on the 19S regulatory subunit RPN1. Covalent modification of proteins with the cytokine inducible ubiquitin-like modifier FAT10 is an alternative signal for proteasomal degradation. Here, we report that FAT10 and its interaction partner NUB1L facilitate the gate opening of the 20S proteasome in an ubiquitin- and USP14-independent manner. We also show that FAT10 is capable to activate all peptidolytic activities of the 26S proteasome, however only together with NUB1L, by binding to the UBA domains of NUB1L and thereby interfering with NUB1L dimerization. The binding of FAT10 to NUB1L leads to an increased affinity of NUB1L for the subunit RPN1. In conclusion, the herein described cooperation of FAT10 and NUB1L is a substrate-induced mechanism to activate the 26S proteasome.

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Kimura, Yayoi, Yasushi Saeki, Hideyoshi Yokosawa, Bogdan Polevoda, Fred Sherman, and Hisashi Hirano. "N-Terminal modifications of the 19S regulatory particle subunits of the yeast proteasome." Archives of Biochemistry and Biophysics 409, no. 2 (January 2003): 341–48. http://dx.doi.org/10.1016/s0003-9861(02)00639-2.

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12

Saeki, Yasushi, Akio Toh-e, Tai Kudo, Hitomi Kawamura, and Keiji Tanaka. "Multiple Proteasome-Interacting Proteins Assist the Assembly of the Yeast 19S Regulatory Particle." Cell 137, no. 5 (May 2009): 900–913. http://dx.doi.org/10.1016/j.cell.2009.05.005.

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13

Zhang, Xiaonan, Stig Linder, and Martina Bazzaro. "Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers." Cancers 12, no. 4 (April 7, 2020): 902. http://dx.doi.org/10.3390/cancers12040902.

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin–proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.

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Bailly, Eric, and Steven I. Reed. "Functional Characterization of Rpn3 Uncovers a Distinct 19S Proteasomal Subunit Requirement for Ubiquitin-Dependent Proteolysis of Cell Cycle Regulatory Proteins in Budding Yeast." Molecular and Cellular Biology 19, no. 10 (October 1, 1999): 6872–90. http://dx.doi.org/10.1128/mcb.19.10.6872.

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ABSTRACT By selectively eliminating ubiquitin-conjugated proteins, the 26S proteasome plays a pivotal role in a large variety of cellular regulatory processes, particularly in the control of cell cycle transitions. Access of ubiquitinated substrates to the inner catalytic chamber within the 20S core particle is mediated by the 19S regulatory particle (RP), whose subunit composition in budding yeast has been recently elucidated. In this study, we have investigated the cell cycle defects resulting from conditional inactivation of one of these RP components, the essential non-ATPase Rpn3/Sun2 subunit. Using temperature-sensitive mutant alleles, we show thatrpn3 mutations do not prevent the G1/S transition but cause a metaphase arrest, indicating that the essential Rpn3 function is limiting for mitosis. rpn3 mutants appear severely compromised in the ubiquitin-dependent proteolysis of several physiologically important proteasome substrates. Thus,RPN3 function is required for the degradation of the G1-phase cyclin Cln2 targeted by SCF; the S-phase cyclin Clb5, whose ubiquitination is likely to involve a combination of E3 (ubiquitin protein ligase) enzymes; and anaphase-promoting complex targets, such as the B-type cyclin Clb2 and the anaphase inhibitor Pds1. Our results indicate that the Pds1 degradation defect of therpn3 mutants most likely accounts for the metaphase arrest phenotype observed. Surprisingly, but consistent with the lack of a G1 arrest phenotype in thermosensitive rpn3 strains, the Cdk inhibitor Sic1 exhibits a short half-life regardless of the RPN3 genotype. In striking contrast, Sic1 turnover is severely impaired by a temperature-sensitive mutation in RPN12/NIN1, encoding another essential RP subunit. While other interpretations are possible, these data strongly argue for the requirement of distinct RP subunits for efficient proteolysis of specific cell cycle regulators. The potential implications of these data are discussed in the context of possible Rpn3 function in multiubiquitin-protein conjugate recognition by the 19S proteasomal regulatory particle.

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Peng, Zhaohua, Jeffrey M. Staub, Giovanna Serino, Shing F. Kwok, Jasmina Kurepa, Barry D. Bruce, Richard D. Vierstra, Ning Wei, and Xing-Wang Deng. "The Cellular Level of PR500, a Protein Complex Related to the 19S Regulatory Particle of the Proteasome, Is Regulated in Response to Stresses in Plants." Molecular Biology of the Cell 12, no. 2 (February 2001): 383–92. http://dx.doi.org/10.1091/mbc.12.2.383.

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In Arabidopsis seedlings and cauliflower florets, Rpn6 (a proteasome non-ATPase regulatory subunit) was found in two distinct protein complexes of ∼800 and 500 kDa, respectively. The large complex likely represents the proteasome 19S regulator particle (RP) because it displays the expected subunit composition and all characteristics. The small complex, designated PR500, shares at least three subunits with the “lid” subcomplex of 19S RP and is loosely associated with an hsp70 protein. In ArabidopsisCOP9 signalosome mutants, PR500 was specifically absent or reduced to an extent that correlates with the severity of the mutations. Furthermore, PR500 was also diminished in response to potential protein-misfolding stresses caused by the heat shock and canavanine treatment. Immunofluorescence studies suggest that PR500 has a distinct localization pattern and is enriched in specific nuclear foci. We propose that PR500 may be evolved in higher plants to cope with the frequently encountered environmental stresses.

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Rosenzweig, Rina, and Michael H. Glickman. "Chaperone-driven proteasome assembly." Biochemical Society Transactions 36, no. 5 (September 19, 2008): 807–12. http://dx.doi.org/10.1042/bst0360807.

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Assembly of the 34-subunit, 2.5 MDa 26S proteasome is a carefully choreographed intricate process. It starts with formation of a seven-membered α-ring that serves as a template for assembly of the complementary β-ring-forming ‘half-proteasomes’. Dimerization results in a latent 20S core particle that can serve further as a platform for 19S regulatory particle attachment and formation of the biologically active 26S proteasome for ubiquitin-dependent proteolysis. Both general and dedicated proteasome assembly chaperones regulate the efficiency and outcome of critical steps in proteasome biogenesis, and in complex association.

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Buneeva, O. A., A. T. Kopylov, and A. E. Medvedev. "The key role of the regulatory 19S subunit in changes in the brain proteasome subproteome induced by the neuroprotector isatin." Biomeditsinskaya Khimiya 68, no. 4 (2022): 250–62. http://dx.doi.org/10.18097/pbmc20226804250.

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Isatin (indole-2,3-dione) is an endogenous regulator exhibiting various effects mediated by numerous isatin-binding proteins localized in different compartments of cells of the brain and peripheral tissues. It attenuates manifestations of experimental parkinsonism induced by administration of the MPTP neurotoxin and reduces the movement disorders characteristic of this disease. The molecular mechanisms of the neuroprotective action of isatin include its direct interaction with proteasomes, intracellular supramolecular complexes responsible for the targeted elimination of proteins. Incubation of fractions of 26S and 20S rabbit brain proteasomes, containing the whole spectrum of proteasomal subunits, as well as a number of proteasome-associated proteins, with isatin (100 μM) had a significant impact on the profile of released proteins. In the case of 26S proteasomes containing, in addition to the core part (20S proteasome), 19S regulatory subparticles, incubation with isatin resulted in a more than threefold increase in the number of dissociated proteins. In the case of 20S proteasomes (containing only the 20S core particle), incubation with isatin resulted in a significant decrease in the number of dissociated proteins compared to the control. Our results indicate an important role of the regulatory 19S subunit components in the formation of the proteasome subproteome and the sensitivity of these supramolecular complexes to isatin.

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Le Tallec, Benoît, Marie-Bénédicte Barrault, Raphaël Guérois, Thibault Carré, and Anne Peyroche. "Hsm3/S5b Participates in the Assembly Pathway of the 19S Regulatory Particle of the Proteasome." Molecular Cell 33, no. 3 (February 2009): 389–99. http://dx.doi.org/10.1016/j.molcel.2009.01.010.

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Winkler, L. L., J. Hwang, and R. F. Kalejta. "Ubiquitin-Independent Proteasomal Degradation of Tumor Suppressors by Human Cytomegalovirus pp71 Requires the 19S Regulatory Particle." Journal of Virology 87, no. 8 (February 13, 2013): 4665–71. http://dx.doi.org/10.1128/jvi.03301-12.

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Steinberger, Shirel, Julia Adler, and Yosef Shaul. "Method of Monitoring 26S Proteasome in Cells Revealed the Crucial Role of PSMA3 C-Terminus in 26S Integrity." Biomolecules 13, no. 6 (June 15, 2023): 992. http://dx.doi.org/10.3390/biom13060992.

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Proteasomes critically regulate proteostasis via protein degradation. Proteasomes are multi-subunit complexes composed of the 20S proteolytic core particle (20S CP) that, in association with one or two 19S regulatory particles (19S RPs), generates the 26S proteasome, which is the major proteasomal complex in cells. Native gel protocols are used to investigate the 26S/20S ratio. However, a simple method for detecting these proteasome complexes in cells is missing. To this end, using CRISPR technology, we YFP-tagged the endogenous PSMB6 (β1) gene, a 20S CP subunit, and co-tagged endogenous PSMD6 (Rpn7), a 19S RP subunit, with the mScarlet fluorescent protein. We observed the colocalization of the YFP and mScarlet fluorescent proteins in the cells, with higher nuclear accumulation. Nuclear proteasomal granules are formed under osmotic stress, and all were positive for YFP and mScarlet. Previously, we have reported that PSMD1 knockdown, one of the 19 RP subunits, gives rise to a high level of “free” 20S CPs. Intriguingly, under this condition, the 20S-YFP remained nuclear, whereas the PSMD6-mScarlet was mostly in cytoplasm, demonstrating the distinct subcellular distribution of uncapped 20S CPs. Lately, we have shown that the PSMA3 (α7) C-terminus, a 20S CP subunit, binds multiple intrinsically disordered proteins (IDPs). Remarkably, the truncation of the PSMA3 C-terminus is phenotypically reminiscent of PSMD1 knockdown. These data suggest that the PSMA3 C-terminal region is critical for 26S proteasome integrity.

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Marquez-Lona, Esther Magdalena, Ana Lilia Torres-Machorro, Frankie R. Gonzales, Lorraine Pillus, and Gentry N. Patrick. "Phosphorylation of the 19S regulatory particle ATPase subunit, Rpt6, modifies susceptibility to proteotoxic stress and protein aggregation." PLOS ONE 12, no. 6 (June 29, 2017): e0179893. http://dx.doi.org/10.1371/journal.pone.0179893.

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22

Ferdous, Anwarul, Fernando Gonzalez, Liping Sun, Thomas Kodadek, and Stephen Albert Johnston. "The 19S Regulatory Particle of the Proteasome Is Required for Efficient Transcription Elongation by RNA Polymerase II." Molecular Cell 7, no. 5 (May 2001): 981–91. http://dx.doi.org/10.1016/s1097-2765(01)00250-7.

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Truax, Agnieszka Dorota, and Susanna F. Greer. "The role of the 19S ATPase S6a in the transcriptional regulation of major histocompatibility class II (MHC II) genes (35.26)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S6. http://dx.doi.org/10.4049/jimmunol.178.supp.35.26.

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Abstract MHC II molecules are glycoproteins that present intracellular antigens to CD4+ T cells and play an important role in induction and regulation of adaptive immune responses. MHC II molecules are regulated at the level of transcription by a master regulator, the class II transcriptional activator, CIITA, whose association with the MHC promoter is necessary for initiation of transcription. It is well established that one mechanism of regulating transcription is through degradation of factors by the 26S proteasome. The proteasome is composed of a 19S regulatory particle that recognizes ubiquitinated proteins and a 20S proteolytic core where the tagged proteins are degraded. Previous studies in yeast have demonstrated that the S6a ATPase of the 19S associates with actively transcribed genes, suggesting a non-degradative role for the ubiquitin-proteasome machinery. To further understand these roles in mammalian cells, we have investigated the role of S6a in regulating CIITA mediated MHC II transcription. Our research indicates that S6a is recruited to actively transcribing MHC II and CIITA genes and that RNAi mediated S6a knockdown correlates with decreased expression of MHC II and CIITA. Our study demonstrates a novel mechanism of regulating MHC II expression and will enhance our understanding of mammalian transcription. Research supported by the NMSS, the Georgia Cancer Coalition and GSU.

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Boehringer, Jonas, Christiane Riedinger, Konstantinos Paraskevopoulos, Eachan O. D. Johnson, Edward D. Lowe, Christina Khoudian, Dominique Smith, Martin E. M. Noble, Colin Gordon, and Jane A. Endicott. "Structural and functional characterization of Rpn12 identifies residues required for Rpn10 proteasome incorporation." Biochemical Journal 448, no. 1 (October 18, 2012): 55–65. http://dx.doi.org/10.1042/bj20120542.

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The ubiquitin–proteasome system targets selected proteins for degradation by the 26S proteasome. Rpn12 is an essential component of the 19S regulatory particle and plays a role in recruiting the extrinsic ubiquitin receptor Rpn10. In the present paper we report the crystal structure of Rpn12, a proteasomal PCI-domain-containing protein. The structure helps to define a core structural motif for the PCI domain and identifies potential sites through which Rpn12 might form protein–protein interactions. We demonstrate that mutating residues at one of these sites impairs Rpn12 binding to Rpn10 in vitro and reduces Rpn10 incorporation into proteasomes in vivo.

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Kao, Athit, Arlo Randall, Yingying Yang, Vishal R. Patel, Wynne Kandur, Shenheng Guan, Scott D. Rychnovsky, Pierre Baldi, and Lan Huang. "Mapping the Structural Topology of the Yeast 19S Proteasomal Regulatory Particle Using Chemical Cross-linking and Probabilistic Modeling." Molecular & Cellular Proteomics 11, no. 12 (April 30, 2012): 1566–77. http://dx.doi.org/10.1074/mcp.m112.018374.

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Otsubo, Ryota, Hitomi Mimuro, Hiroshi Ashida, Jun Hamazaki, Shigeo Murata, and Chihiro Sasakawa. "Shigellaeffector IpaH4.5 targets 19S regulatory particle subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation." Cellular Microbiology 21, no. 3 (December 5, 2018): e12974. http://dx.doi.org/10.1111/cmi.12974.

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Divald, Andras, Shaye Kivity, Ping Wang, Edith Hochhauser, Beth Roberts, Saul Teichberg, Aldrin V. Gomes, and Saul R. Powell. "Myocardial Ischemic Preconditioning Preserves Postischemic Function of the 26S Proteasome Through Diminished Oxidative Damage to 19S Regulatory Particle Subunits." Circulation Research 106, no. 12 (June 25, 2010): 1829–38. http://dx.doi.org/10.1161/circresaha.110.219485.

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Bai, Minghui, Xian Zhao, Kazutaka Sahara, Yuki Ohte, Yuko Hirano, Takeumi Kaneko, Hideki Yashiroda, and Shigeo Murata. "In-depth Analysis of the Lid Subunits Assembly Mechanism in Mammals." Biomolecules 9, no. 6 (May 31, 2019): 213. http://dx.doi.org/10.3390/biom9060213.

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The 26S proteasome is a key player in the degradation of ubiquitinated proteins, comprising a 20S core particle (CP) and a 19S regulatory particle (RP). The RP is further divided into base and lid subcomplexes, which are assembled independently from each other. We have previously demonstrated the assembly pathway of the CP and the base by observing assembly intermediates resulting from knockdowns of each proteasome subunit and the assembly chaperones. In this study, we examine the assembly pathway of the mammalian lid, which remains to be elucidated. We show that the lid assembly pathway is conserved between humans and yeast. The final step is the incorporation of Rpn12 into the assembly intermediate consisting of two modular complexes, Rpn3-7-15 and Rpn5-6-8-9-11, in both humans and yeast. Furthermore, we dissect the assembly pathways of the two modular complexes by the knockdown of each lid subunit.

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Matias, Ana C., Paula C. Ramos, and R. Jürgen Dohmen. "Chaperone-assisted assembly of the proteasome core particle." Biochemical Society Transactions 38, no. 1 (January 19, 2010): 29–33. http://dx.doi.org/10.1042/bst0380029.

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The 26S proteasome is a non-lysosomal protease in the cytosol and nucleus of eukaryotic cells. Its main function is to mediate ubiquitin-dependent proteolysis. The 26S proteasome is a multimeric complex composed by the 20S proteasome CP (core particle) and the 19S RPs (regulatory particles). Although the atomic structure of the 26S proteasome has not yet been determined, high-resolution structures are available for its CP. Studies on the complicated assembly pathway of the proteasome have revealed that it involves an unprecedented number of dedicated chaperones. Assembly of the CP alone involves three conserved proteasome-assembly chaperones [PAC1–PAC2, PAC3–PAC4 and UMP1 (ubiquitin-mediated proteolysis 1)]. Whereas the two heterodimeric PACs have been implicated in the formation of rings of the seven distinct α subunits, UMP1 is important for the formation and dimerization of proteasome precursor complexes containing β subunits. Dimerization coincides with the incorporation of the last β subunit (β7). Additional modules important for the assembly of precursor complexes and their dimerization reside in the β subunits themselves, either as transient or as permanent extensions. Particularly important domains are the propeptide of β5 and the C-terminal extensions of β2 and β7. Upon maturation of the active sites by autocatalytic processing, UMP1 is degraded by the native proteasome.

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Tonoki, Ayako, Erina Kuranaga, Takeyasu Tomioka, Jun Hamazaki, Shigeo Murata, Keiji Tanaka, and Masayuki Miura. "Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process." Molecular and Cellular Biology 29, no. 4 (December 15, 2008): 1095–106. http://dx.doi.org/10.1128/mcb.01227-08.

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ABSTRACT The intracellular accumulation of unfolded or misfolded proteins is believed to contribute to aging and age-related neurodegenerative diseases. However, the links between age-dependent proteotoxicity and cellular protein degradation systems remain poorly understood. Here, we show that 26S proteasome activity and abundance attenuate with age, which is associated with the impaired assembly of the 26S proteasome with the 19S regulatory particle (RP) and the 20S proteasome. In a genetic gain-of-function screen, we characterized Rpn11, which encodes a subunit of the 19S RP, as a suppressor of expanded polyglutamine-induced progressive neurodegeneration. Rpn11 overexpression suppressed the age-related reduction of the 26S proteasome activity, resulting in the extension of flies' life spans with suppression of the age-dependent accumulation of ubiquitinated proteins. On the other hand, the loss of function of Rpn11 caused an early onset of reduced 26S proteasome activity and a premature age-dependent accumulation of ubiquitinated proteins. It also caused a shorter life span and an enhanced neurodegenerative phenotype. Our results suggest that maintaining the 26S proteasome with age could extend the life span and suppress the age-related progression of neurodegenerative diseases.

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Sun, Shuangwu, Sisi Liu, Zhengmao Zhang, Wang Zeng, Chuang Sun, Tao Tao, Xia Lin, and Xin-Hua Feng. "Phosphatase UBLCP1 controls proteasome assembly." Open Biology 7, no. 5 (May 2017): 170042. http://dx.doi.org/10.1098/rsob.170042.

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Ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1), an FCP/SCP phosphatase family member, was identified as the first proteasome phosphatase. UBLCP1 binds to proteasome subunit Rpn1 and dephosphorylates the proteasome in vitro . However, it is still unclear which proteasome subunit(s) are the bona fide substrate(s) of UBLCP1 and the precise mechanism for proteasome regulation remains elusive. Here, we show that UBLCP1 selectively binds to the 19S regulatory particle (RP) through its interaction with Rpn1, but not the 20S core particle (CP) or the 26S proteasome holoenzyme. In the RP, UBLCP1 dephosphorylates the subunit Rpt1, impairs its ATPase activity, and consequently disrupts the 26S proteasome assembly, yet it has no effects on the RP assembly from precursor complexes. The Rpn1-binding and phosphatase activities of UBLCP1 are essential for its function on Rpt1 dephosphorylation and proteasome activity both in vivo and in vitro . Our study establishes the essential role of the UBLCP1/Rpn1/Rpt1 complex in regulating proteasome assembly.

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Yue, Xin, Yinglin Zuo, Hongpeng Ke, Jiaming Luo, Lanlan Lou, Wenjing Qin, Youqiao Wang, et al. "Identification of 4-arylidene curcumin analogues as novel proteasome inhibitors for potential anticancer agents targeting 19S regulatory particle associated deubiquitinase." Biochemical Pharmacology 137 (August 2017): 29–50. http://dx.doi.org/10.1016/j.bcp.2017.04.032.

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33

Takahashi, M., H. Iwasaki, H. Inoue, and K. Takahashi. "Reverse Genetic Analysis of the Caenorhabditis elegans 26S Proteasome Subunits by RNA Interference." Biological Chemistry 383, no. 7-8 (August 27, 2002): 1263–66. http://dx.doi.org/10.1515/bc.2002.140.

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Abstract Reverse genetic analysis was performed on the Caenorhabditis elegans 26S proteasome subunit genes by doublestranded RNAmediated interference (RNAi). Embryonic and postembryonic lethality was caused by interference of all of the eight tested 20S core subunits and all of the 19S regulatory particle subunits except for CeRpn9, CeRpn10, and Ce Rpn12, where RNAi caused no abnormality. However, synthetic suppression of CeRpn10 and CeRpn12 was lethal, whereas neither the combination of Ce Rpn9 with CeRpn10 nor with CeRpn12 resulted in abnormalities in RNAi. These results indicate that the 26S proteasome is indispensable for embryogenesis and postembryonic development, although Ce Rpn9, CeRpn10, and CeRpn12 are not essential, at least under the conditions used. CeRpn10 and Ce Rpn12 are considered to compensate for the suppression of each other.

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Bustamante, Hianara A., Karina Cereceda, Alexis E. González, Guillermo E. Valenzuela, Yorka Cheuquemilla, Sergio Hernández, Eloisa Arias-Muñoz, et al. "The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport." Cells 9, no. 3 (March 23, 2020): 777. http://dx.doi.org/10.3390/cells9030777.

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Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of the human “ubiquitinome” using amyloid precursor protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 with Capzimin (CZM) caused a robust increase in APP levels at the Golgi apparatus and the swelling of this organelle. We showed that this phenotype is the result of rapid inhibition of Golgi-to-ER retrograde transport, a pathway implicated in the early steps of the autophagosomal formation. Indeed, we observed that inhibition of PSMD14 with CZM acts as a potent blocker of macroautophagy by a mechanism related to the retention of Atg9A and Rab1A at the Golgi apparatus. As pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and the K63-Ub chains, act as a crucial regulatory factor for macroautophagy by controlling Golgi-to-ER retrograde transport.

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Liu, Xiaoyan, Weidi Xiao, Yanan Zhang, Sandra E. Wiley, Tao Zuo, Yingying Zheng, Natalie Chen, et al. "Reversible phosphorylation of Rpn1 regulates 26S proteasome assembly and function." Proceedings of the National Academy of Sciences 117, no. 1 (December 16, 2019): 328–36. http://dx.doi.org/10.1073/pnas.1912531117.

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The fundamental importance of the 26S proteasome in health and disease suggests that its function must be finely controlled, and yet our knowledge about proteasome regulation remains limited. Posttranslational modifications, especially phosphorylation, of proteasome subunits have been shown to impact proteasome function through different mechanisms, although the vast majority of proteasome phosphorylation events have not been studied. Here, we have characterized 1 of the most frequently detected proteasome phosphosites, namely Ser361 of Rpn1, a base subunit of the 19S regulatory particle. Using a variety of approaches including CRISPR/Cas9-mediated gene editing and quantitative mass spectrometry, we found that loss of Rpn1-S361 phosphorylation reduces proteasome activity, impairs cell proliferation, and causes oxidative stress as well as mitochondrial dysfunction. A screen of the human kinome identified several kinases including PIM1/2/3 that catalyze S361 phosphorylation, while its level is reversibly controlled by the proteasome-resident phosphatase, UBLCP1. Mechanistically, Rpn1-S361 phosphorylation is required for proper assembly of the 26S proteasome, and we have utilized a genetic code expansion system to directly demonstrate that S361-phosphorylated Rpn1 more readily forms a precursor complex with Rpt2, 1 of the first steps of 19S base assembly. These findings have revealed a prevalent and biologically important mechanism governing proteasome formation and function.

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Lim, Hyun-Suk, Di Cai, Chase T. Archer, and Thomas Kodadek. "Periodate-Triggered Cross-Linking Reveals Sug2/Rpt4 as the Molecular Target of a Peptoid Inhibitor of the 19S Proteasome Regulatory Particle." Journal of the American Chemical Society 129, no. 43 (October 2007): 12936–37. http://dx.doi.org/10.1021/ja075469+.

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Shibahara, Tadashi, Hiroshi Kawasaki, and Hisashi Hirano. "Mass spectrometric analysis of expression of ATPase subunits encoded by duplicated genes in the 19S regulatory particle of rice 26S proteasome." Archives of Biochemistry and Biophysics 421, no. 1 (January 2004): 34–41. http://dx.doi.org/10.1016/j.abb.2003.10.013.

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Gu, Yanyan, Benjamin G. Barwick, Mala Shanmugam, Craig C. Hofmeister, Jonathan L. Kaufman, Ajay K. Nooka, Vikas A. Gupta, Madhav V. Dhodapkar, Lawrence H. Boise, and Sagar Lonial. "The Role of Proteasome Activator PA28α in Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 5499. http://dx.doi.org/10.1182/blood-2019-128216.

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Multiple myeloma (MM) is a commonly occurring hematologic malignancy in the United States with poor prognosis. Among all treatments, proteasome inhibitor (PI) based regimens have been a major breakthrough for patients' outcomes. Available PIs all target 20S proteasome core complex, and the duration of response is limited by toxicity and resistance development. Until now, the underlying mechanism of drug resistance remains unclear. The proteasome is the major proteolytic machinery in protein homeostasis which is pivotal for myeloma cell survival. A functional proteasome consists of 20S proteasome core particle with regulatory particle on one or both ends. There are 3 types of proteasome regulators that could activate a 20S proteasome, PA700 (19S), 11S REG (PA28) and PA200. The 11S REG (PA28) protein family consists of three members, α, β, and γ. PA28 α/β are IFN-γ inducible and with higher expression in antigen presenting cells. Currently, the function of 11S subunit remains largely unknown. Our analysis of plasma cells from MM patients and healthy donors has demonstrated that expression of 11S proteasome is higher in myeloma cells than normal plasma cells and progressively upregulated with disease progression. To further identify the function of 11S proteasome especially PA28α in MM, we generate PA28α knockdown stable MM cell lines. We have found that knockdown of PA28α inhibits MM cell growth and proliferation, also induces myeloma cell resistance to PIs. The mechanism of PI resistance is different from knocking down of 19S or 20S proteasome subunits. Silencing of PA28α inhibits proteasome activity and decreases proteasome work load concurrently, resulting in a favorable proteasome load vs capacity ratio. Altogether, in this report, we describe the function of PA28α in MM cells, also provide novel insights into regulating PIs sensitivity through modulation of the 11S proteasome subunit PA28α. Disclosures Hofmeister: Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Kaufman:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; AbbVie: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy. Nooka:Amgen: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation. Boise:Genentech Inc.: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Research Funding. Lonial:Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy, Research Funding.

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Diao, Wentao, Xue Yang, and Hao Zhou. "Purification, crystallization and preliminary X-ray data collection of the N-terminal domain of the 26S proteasome regulatory subunit p27 and its complex with the ATPase domain of Rpt5 fromMus musculus." Acta Crystallographica Section F Structural Biology Communications 70, no. 5 (April 15, 2014): 611–15. http://dx.doi.org/10.1107/s2053230x14006815.

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The protein 26S proteasome regulatory subunit p27 is one of the four chaperones that help in the assembly of the 19S regulatory particle (RP) of the 26S proteasome. In the present work, the N-terminus of p27 (residues 1–128) fromMus musculuswas cloned, expressed, purified and crystallized alone and in complex with the C-terminal ATPase domain of Rpt5 (residues 173–442). The crystals of p27(1–128)diffracted to 1.7 Å resolution and belonged to space groupP212121, with unit-cell parametersa= 26.79,b= 30.39,c= 145.06 Å. Resolution-dependent Matthews coefficient probability analysis suggested the presence of only one molecule per asymmetric unit, with 40.5% solvent content and aVMvalue of 2.02 Å3 Da−1. The crystal of the p27(1–128)–Rpt5(173–442)complex diffracted to 4 Å resolution and belonged to space groupP222, with unit-cell parametersa= 75.93,b= 76.08,c= 336.85 Å. The presence of four heterodimers in the asymmetric unit with 53.2% solvent content and aVMvalue of 2.63 Å3 Da−1or five heterodimers in the asymmetric unit with 41.5% solvent content and aVMvalue of 2.10 Å3 Da−1is assumed.

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Song, Yan, Arghya Ray, Deepika Sharma DAS, Dharminder Chauhan, and Kenneth C. Anderson. "Targeting 19S-Proteasome Deubiquitinase Rpn11/POH1/PSMD14 in Multiple Myeloma." Blood 126, no. 23 (December 3, 2015): 1811. http://dx.doi.org/10.1182/blood.v126.23.1811.1811.

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Abstract Introduction Deregulation of the ubiquitin-proteasome system (UPS) is linked to pathogenesis of various human diseases, including cancer. Targeting the proteasome is an effective therapy in multiple myeloma (MM) patients. Recent research efforts led to the discovery of newer agents that target enzymes modulating protein ubiquitin-conjugation/deconjugation rather than the proteasome itself, with the goal of generating more specific and less toxic antitumor therapies. Ubiquitylation is a dynamic reversible process coordinated by many enzymes: ubiquitin ligases attach ubiquitin to proteins allowing for their degradation, whereas deubiquitylating (DUB) enzymes deconjugate ubiquitin from target proteins, thereby preventing their proteasome-mediated degradation. Rpn11 is a DUB enzyme associated with the 19S regulatory particle lid of the proteasome that removes ubiquitin from target proteins to facilitate protein degradation by 20S proteasome core particle. Here we examined the role of Rpn11 in MM using both biochemical and RNA interference strategies. Materials and Methods Cell viability and apoptosis were assessed using WST and Annexin V staining, respectively. MM.1S MM cells were transiently transfected with control short interfering RNA (siRNA), RPN11 ON TARGET plus SMART pool siRNA using the cell line Nucleofector Kit V. Isobologram analysisand CalcuSyn software program were utilized to assesssynergistic/additive anti-MM activity. Ub-AMC assay Proteasome activity was measured, as in our prior study (Chauhan et al., Cancer Cell 2005, 8:407-419). Signal transduction pathways were evaluated using immunoblotting. Statistical significance of data was determined using a Student's t test. O-phenanthroline (OPA) was purchased from EMD Millipore, USA; and bortezomib, lenalidomide, and pomalidomide were purchased from Selleck chemicals, USA. Results Gene expression (GEP) analysis of Rpn11 showed a significantly higher level in primary patient MM cells (n=73) versus normal plasma cells (n=15) (p < 0.05). We found a statistically significant inverse correlation between Rpn11 levels and overall patient survival (p =0.035). Western blot analyses show higher Rpn11 levels in MM cell lines and patient cells compared to normal cells. Rpn11-siRNA significantly decreased MM cell viability (p < 0.001; n=3). To further validate our siRNA data, we utilized Rpn11 inhibitor O-phenanthroline (OPA) (Verma et al., Science 2002, 298:611-5). Treatment of MM cell lines (MM.1S, MM.1R, RPMI-8226, ARP-1, Dox40, LR5, INA6, ANBL6.WT, and ANBL6.BR) and primary patient cells for 48h significantly decreased their viability (IC50 range 8µM to 60µM; p < 0.001 for all cell lines; n=3) without markedly affecting PBMCs from normal healthy donors, suggesting specific anti-MM activity and a favorable therapeutic index for OPA. Tumor cells obtained from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies remained sensitive to OPA. Moreover, the cytotoxicity of OPA was observed in MM cell lines sensitive and resistant to conventional (dex) and novel (bortezomib) therapies. Furthermore, OPA inhibits proliferation of MM cells even in the presence of BM stromal cells or pDCs. OPA inhibits Rpn11 DUB activity without blocking 20S proteasome activities. Mechanistic studies show that OPA-triggered MM cell death is associated with 1) accumulation of cells in early and late apoptotic phase; 2) increase in polyubiquinated proteins; and 3) activation of caspases mediating both intrinsic and extrinsic apoptotic pathways. Importantly, OPA-induced apoptosis in MM cells occurs in a p53-independent manner, since OPA triggered significant apoptosis in both p53-null (ARP-1) and p53-mutant (RPMI-8226) MM cells (p < 0.004). Finally, combining OPA with lenalidomide, pomalidomide, or bortezomib induces synergistic/additive anti-MM activity, and overcomes drug resistance. Conclusion Our preclinical data showing efficacy of OPA in MM disease models validates targeting 19S proteasome-associated DUB Rpn11 upstream of the proteasome in the ubiquitin proteasomal cascade to overcome proteasome inhibitor resistance, and provides the framework for clinical evaluation of Rpn11 inhibitors to improve patient outcome in MM. Disclosures Chauhan: Stemline Therapeutics: Consultancy.

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Kuo, Chueh-Ling, and Alfred Lewis Goldberg. "Ubiquitinated proteins promote the association of proteasomes with the deubiquitinating enzyme Usp14 and the ubiquitin ligase Ube3c." Proceedings of the National Academy of Sciences 114, no. 17 (April 10, 2017): E3404—E3413. http://dx.doi.org/10.1073/pnas.1701734114.

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In mammalian cells, the 26S proteasomes vary in composition. In addition to the standard 28 subunits in the 20S core particle and 19 subunits in each 19S regulatory particle, a small fraction (about 10–20% in our preparations) also contains the deubiquitinating enzyme Usp14/Ubp6, which regulates proteasome activity, and the ubiquitin ligase, Ube3c/Hul5, which enhances proteasomal processivity. When degradation of ubiquitinated proteins in cells was inhibited, levels of Usp14 and Ube3c on proteasomes increased within minutes. Conversely, when protein ubiquitination was prevented, or when purified proteasomes hydrolyzed the associated ubiquitin conjugates, Usp14 and Ube3c dissociated rapidly (unlike other 26S subunits), but the inhibitor ubiquitin aldehyde slowed their dissociation. Recombinant Usp14 associated with purified proteasomes preferentially if they contained ubiquitin conjugates. In cells or extracts, adding Usp14 inhibitors (IU-1 or ubiquitin aldehyde) enhanced Usp14 and Ube3c binding further. Thus, in the substrate- or the inhibitor-bound conformations, Usp14 showed higher affinity for proteasomes and surprisingly enhanced Ube3c binding. Moreover, adding ubiquitinated proteins to cell extracts stimulated proteasome binding of both enzymes. Thus, Usp14 and Ube3c cycle together on and off proteasomes, and the presence of ubiquitinated substrates promotes their association. This mechanism enables proteasome activity to adapt to the supply of substrates.

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Xia, Xue, Chun-Meng Tang, Gu-Zi Chen, and Jia-Jia Han. "Proteasome Dysfunction Leads to Suppression of the Hypoxic Response Pathway in Arabidopsis." International Journal of Molecular Sciences 23, no. 24 (December 18, 2022): 16148. http://dx.doi.org/10.3390/ijms232416148.

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Proteasome is a large proteolytic complex that consists of a 20S core particle (20SP) and 19S regulatory particle (19SP) in eukaryotes. The proteasome degrades most cellular proteins, thereby controlling many key processes, including gene expression and protein quality control. Proteasome dysfunction in plants leads to abnormal development and reduced adaptability to environmental stresses. Previous studies have shown that proteasome dysfunction upregulates the gene expression of proteasome subunits, which is known as the proteasome bounce-back response. However, the proteasome bounce-back response cannot explain the damaging effect of proteasome dysfunction on plant growth and stress adaptation. To address this question, we focused on downregulated genes caused by proteasome dysfunction. We first confirmed that the 20SP subunit PBE is an essential proteasome subunit in Arabidopsis and that PBE1 mutation impaired the function of the proteasome. Transcriptome analyses showed that hypoxia-responsive genes were greatly enriched in the downregulated genes in pbe1 mutants. Furthermore, we found that the pbe1 mutant is hypersensitive to waterlogging stress, a typical hypoxic condition, and hypoxia-related developments are impaired in the pbe1 mutant. Meanwhile, the 19SP subunit rpn1a mutant seedlings are also hypersensitive to waterlogging stress. In summary, our results suggested that proteasome dysfunction downregulated the hypoxia-responsive pathway and impaired plant growth and adaptability to hypoxia stress.

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Sahu, Indrajit, and Michael H. Glickman. "Proteasome in action: substrate degradation by the 26S proteasome." Biochemical Society Transactions 49, no. 2 (March 17, 2021): 629–44. http://dx.doi.org/10.1042/bst20200382.

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Ubiquitination is the major criteria for the recognition of a substrate-protein by the 26S proteasome. Additionally, a disordered segment on the substrate — either intrinsic or induced — is critical for proteasome engagement. The proteasome is geared to interact with both of these substrate features and prepare it for degradation. To facilitate substrate accessibility, resting proteasomes are characterised by a peripheral distribution of ubiquitin receptors on the 19S regulatory particle (RP) and a wide-open lateral surface on the ATPase ring. In this substrate accepting state, the internal channel through the ATPase ring is discontinuous, thereby obstructing translocation of potential substrates. The binding of the conjugated ubiquitin to the ubiquitin receptors leads to contraction of the 19S RP. Next, the ATPases engage the substrate at a disordered segment, energetically unravel the polypeptide and translocate it towards the 20S catalytic core (CP). In this substrate engaged state, Rpn11 is repositioned at the pore of the ATPase channel to remove remaining ubiquitin modifications and accelerate translocation. C-termini of five of the six ATPases insert into corresponding lysine-pockets on the 20S α-ring to complete 20S CP gate opening. In the resulting substrate processing state, the ATPase channel is fully contiguous with the translocation channel into the 20S CP, where the substrate is proteolyzed. Complete degradation of a typical ubiquitin-conjugate takes place over a few tens of seconds while hydrolysing tens of ATP molecules in the process (50 kDa/∼50 s/∼80ATP). This article reviews recent insight into biochemical and structural features that underlie substrate recognition and processing by the 26S proteasome.

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Muller, D. "A molecular link A molecular link between Hairless and Pros26.4, a member of the AAA-ATPase subunits of the proteasome 19S regulatory particle in Drosophila." Journal of Cell Science 119, no. 2 (January 15, 2006): 250–58. http://dx.doi.org/10.1242/jcs.02743.

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Cekała, Katarzyna, Karolina Trepczyk, Julia Witkowska, Elżbieta Jankowska, and Ewa Wieczerzak. "Rpt5-Derived Analogs Stimulate Human Proteasome Activity in Cells and Degrade Proteins Forming Toxic Aggregates in Age-Related Diseases." International Journal of Molecular Sciences 25, no. 9 (April 25, 2024): 4663. http://dx.doi.org/10.3390/ijms25094663.

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Aging and age-related diseases are associated with a decline in the capacity of protein turnover. Intrinsically disordered proteins, as well as proteins misfolded and oxidatively damaged, prone to aggregation, are preferentially digested by the ubiquitin-independent proteasome system (UIPS), a major component of which is the 20S proteasome. Therefore, boosting 20S activity constitutes a promising strategy to counteract a decrease in total proteasome activity during aging. One way to enhance the proteolytic removal of unwanted proteins appears to be the use of peptide-based activators of the 20S. In this study, we synthesized a series of peptides and peptidomimetics based on the C-terminus of the Rpt5 subunit of the 19S regulatory particle. Some of them efficiently stimulated human 20S proteasome activity. The attachment of the cell-penetrating peptide TAT allowed them to penetrate the cell membrane and stimulate proteasome activity in HEK293T cells, which was demonstrated using a cell-permeable substrate of the proteasome, TAS3. Furthermore, the best activator enhanced the degradation of aggregation-prone α-synuclein and Tau-441. The obtained compounds may therefore have the potential to compensate for the unbalanced proteostasis found in aging and age-related diseases.

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McDonald, Heather B., Astrid Hoes Helfant, Erin M. Mahony, Shaun K. Khosla, and Loretta Goetsch. "Mutational Analysis Reveals a Role for the C Terminus of the Proteasome Subunit Rpt4p in Spindle Pole Body Duplication inSaccharomyces cerevisiae." Genetics 162, no. 2 (October 1, 2002): 705–20. http://dx.doi.org/10.1093/genetics/162.2.705.

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AbstractThe ubiquitin/proteasome pathway plays a key role in regulating cell cycle progression. Previously, we reported that a conditional mutation in the Saccharomyces cerevisiae gene RPT4/PCS1, which encodes one of six ATPases in the proteasome 19S cap complex/regulatory particle (RP), causes failure of spindle pole body (SPB) duplication. To improve our understanding of Rpt4p, we created 58 new mutations, 53 of which convert clustered, charged residues to alanine. Virtually all mutations that affect the N-terminal region, which contains a putative nuclear localization signal and coiled-coil motif, result in a wild-type phenotype. Nine mutations that affect the central ATPase domain and the C-terminal region confer recessive lethality. The two conditional mutations identified, rpt4-145 and rpt4-150, affect the C terminus. After shift to high temperature, these mutations generally cause cells to progress slowly through the first cell cycle and to arrest in the second cycle with large buds, a G2 content of DNA, and monopolar spindles, although this phenotype can vary depending on the medium. Additionally, we describe a genetic interaction between RPT4 and the naturally polymorphic gene SSD1, which in wild-type form modifies the rpt4-145 phenotype such that cells arrest in G2 of the first cycle with complete bipolar spindles.

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Li, Shuyu, Robert A. Spooner, Stuart C. H. Allen, Christopher P. Guise, Graham Ladds, Tina Schnöder, Manfred J. Schmitt, J. Michael Lord, and Lynne M. Roberts. "Folding-competent and Folding-defective Forms of Ricin A Chain Have Different Fates after Retrotranslocation from the Endoplasmic Reticulum." Molecular Biology of the Cell 21, no. 15 (August 2010): 2543–54. http://dx.doi.org/10.1091/mbc.e09-08-0743.

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We report that a toxic polypeptide retaining the potential to refold upon dislocation from the endoplasmic reticulum (ER) to the cytosol (ricin A chain; RTA) and a misfolded version that cannot (termed RTAΔ), follow ER-associated degradation (ERAD) pathways in Saccharomyces cerevisiae that substantially diverge in the cytosol. Both polypeptides are dislocated in a step mediated by the transmembrane Hrd1p ubiquitin ligase complex and subsequently degraded. Canonical polyubiquitylation is not a prerequisite for this interaction because a catalytically inactive Hrd1p E3 ubiquitin ligase retains the ability to retrotranslocate RTA, and variants lacking one or both endogenous lysyl residues also require the Hrd1p complex. In the case of native RTA, we established that dislocation also depends on other components of the classical ERAD-L pathway as well as an ongoing ER–Golgi transport. However, the dislocation pathways deviate strikingly upon entry into the cytosol. Here, the CDC48 complex is required only for RTAΔ, although the involvement of individual ATPases (Rpt proteins) in the 19S regulatory particle (RP) of the proteasome, and the 20S catalytic chamber itself, is very different for the two RTA variants. We conclude that cytosolic ERAD components, particularly the proteasome RP, can discriminate between structural features of the same substrate.

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McPherson, Ann, and Tania Watts. "The role of TRAF1 in stabilizing TRAF2 from proteasome mediated degradation downstream of 4-1BB signaling (138.1)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 138.1. http://dx.doi.org/10.4049/jimmunol.184.supp.138.1.

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Abstract TNF receptor family members play important roles in the innate and adaptive immune response, inducing signals for cell survival or apoptosis. This signaling in most cases relies on TNF receptor associated factors (TRAFs) to relay the signal from the TNFR family member to activation of NF-κB or MAPK pathways. Results from our lab have shown that TRAF1 is critical in the downregulation of the proapoptotic molecule Bim and the survival of activated and memory CD8 T cells, acting downstream of the prosurvival TNF receptor family member 4-1BB. We show here that in the absence of TRAF1, signaling downstream of 4-1BB results in the rapid proteasome dependent degradation of TRAF2. To identify interacting binding partners of TRAF1 that may mediate its stabilizing role on TRAF2 we performed a yeast two hybrid screen using a cDNA library from activated mouse lymph nodes. Among the interacting proteins identified were PSMC3, a subunit of the 19S regulatory particle of the 26S proteasome. We have confirmed the interaction between TRAF1 and PSMC3 in T cells and are currently investigating its functional role in the signaling downstream of 4-1BB. The results suggest that TRAF1 may have an important role in controlling the duration of the signal.

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Lokireddy, Sudarsanareddy, Nikolay Vadimovich Kukushkin, and Alfred Lewis Goldberg. "cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins." Proceedings of the National Academy of Sciences 112, no. 52 (December 15, 2015): E7176—E7185. http://dx.doi.org/10.1073/pnas.1522332112.

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Although rates of protein degradation by the ubiquitin-proteasome pathway (UPS) are determined by their rates of ubiquitination, we show here that the proteasome’s capacity to degrade ubiquitinated proteins is also tightly regulated. We studied the effects of cAMP-dependent protein kinase (PKA) on proteolysis by the UPS in several mammalian cell lines. Various agents that raise intracellular cAMP and activate PKA (activators of adenylate cyclase or inhibitors of phosphodiesterase 4) promoted degradation of short-lived (but not long-lived) cell proteins generally, model UPS substrates having different degrons, and aggregation-prone proteins associated with major neurodegenerative diseases, including mutant FUS (Fused in sarcoma), SOD1 (superoxide dismutase 1), TDP43 (TAR DNA-binding protein 43), and tau. 26S proteasomes purified from these treated cells or from control cells and treated with PKA degraded ubiquitinated proteins, small peptides, and ATP more rapidly than controls, but not when treated with protein phosphatase. Raising cAMP levels also increased amounts of doubly capped 26S proteasomes. Activated PKA phosphorylates the 19S subunit, Rpn6/PSMD11 (regulatory particle non-ATPase 6/proteasome subunit D11) at Ser14. Overexpression of a phosphomimetic Rpn6 mutant activated proteasomes similarly, whereas a nonphosphorylatable mutant decreased activity. Thus, proteasome function and protein degradation are regulated by cAMP through PKA and Rpn6, and activation of proteasomes by this mechanism may be useful in treating proteotoxic diseases.

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Song, Yan, Arghya Ray, Dharminder Chauhan, and Kenneth Anderson. "Blockade of Ubiquitin Receptor PSMD4/Rpn10 Triggers Cytotoxicity and Overcomes Bortezomib-Resistance in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 3211. http://dx.doi.org/10.1182/blood-2018-99-114767.

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Abstract Background and Rationale Proteasome inhibitors (PIs) are standard of care therapy for patients diagnosed with multiple myeloma (MM). However, prolonged treatment can be associated with toxicity and development of drug resistance. Our research efforts have therefore focused on designing therapeutic strategies that can overcome PI-resistance. In this context, our RNA-interference-based loss-of-function studies have identified 19S proteasome-associated Ubiquitin Receptor (UbRs) Rpn10 and Rpn13 as potential therapeutic targets. Both Rpn10 and Rpn13 UbRs are associated with the 19S regulatory lid of the proteasome that recognizes ubiquitylated proteins marked for degradation by 20S core particle. We have previously reported the role of Rpn13 in MM (Song et., al Luekemia 2016 Sep;30(9):1877-86). Here we functionally characterized the role of Rpn10 in MM. Materials and Methods Cytotoxicity assays were performed using a panel of MM cell lines, primary patient cells, and peripheral blood mononuclear cells (PBMCs) from normal healthy donors. Cell viability was assessed using WST-1, MTT, and Cell Titer-Glo assay.Signal transduction pathways were evaluated using immunoblotting. Proteasome activity was measured as previously described (Chauhan et al., Cancer Cell 2005, 8:407-419; Chauhan et al., Cancer Cell 2012, 22(3):345-358). Statistical significance of data was determined using a Student's t test. Results Functional characterization of Rpn10 in MM:Gene expression (GEP) analysis showed inverse correlation between Rpn10 and overall patient survival (n=175) (p= 0.00064). Immunoblot analysis showed high Rpn10 protein levels in primary patient cells and MM cell lines versus normal plasma cells or PBMCs. Rpn10 knockdown by siRNA significantly decreased MM cell viability in both bortezomib-sensitive and -resistant MM cell lines. To assess the Rpn10 function, we generated a doxycycline-inducible Rpn10-shRNA knockout stable MM cell line. Rpn10-shRNA knockdown decreased MM cell proliferation. Mechanistic studies show that Rpn10 knockdown-triggered MM cell death is associated with 1) accumulation of cells in early and late apoptotic phase; 2) increase in polyubiquinated proteins; 3) arrest of cell cycle; 4) induction of ER stress; and 5) activation of caspases mediating apoptotic pathways. In order to determine if blockade of Rpn10 affects cellular proteasome function, we next utilized a reporter cell line expressing ubiquitin-tagged GFP that is constitutively targeted for proteasomal degradation. Interestingly, Rpn10-siRNA increased accumulation of the Ub-GFP reporter, reflecting impaired proteasome-mediated protein degradation. Finally, treatment of MM cells with peptides targeting UIM2 domain of Rpn10 significantly decreased MM cell viability, suggesting a potential therapeutic approach in MM. ConclusionOur preclinical data validates targeting 19S proteasome ubiquitin receptor Rpn10 upstream of the proteasome in the ubiquitin proteasomal cascade, and provides the framework for clinical evaluation of Rpn10 inhibitors to overcome PI resistance and improve patient outcome in MM. Disclosures Anderson: C4 Therapeutics: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Consultancy; OncoPep: Equity Ownership, Other: Scientific founder.

Journal articles on the topic '19S regulatory particle'

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