Molular mechanisms of proteasome assembly

Laboratory of Protein Metabolism, Department of Integrated Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 03/2009; 10(2):104-15. DOI: 10.1038/nrm2630
Source: PubMed


The 26S proteasome is a highly conserved protein degradation machine that consists of the 20S proteasome and 19S regulatory particles, which include 14 and 19 different polypeptides, respectively. How the proteasome components are assembled is a fundamental question towards understanding the process of protein degradation and its functions in diverse biological processes. Several proteasome-dedicated chaperones are involved in the efficient and correct assembly of the 20S proteasome. These chaperones help the initiation and progression of the assembly process by transiently associating with proteasome precursors. By contrast, little is known about the assembly of the 19S regulatory particles, but several hints have emerged.

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    • "Proteasome biogenesis is a highly coordinated multistep event involving the synthesis of all subunits, proteasome assembly , and maturation. Proteasome assembly is not autonomous , but requires chaperones (Murata et al., 2009). In yeast, Ump1 was identified as an assembly factor for the 20S proteasome (Ramos et al., 1998). "
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    ABSTRACT: Proteasome inhibition represents a promising strategy of cancer pharmacotherapy, but resistant tumor cells often emerge. Here we show that the microRNA-101 (miR-101) targets the proteasome maturation protein POMP, leading to impaired proteasome assembly and activity, and resulting in accumulation of p53 and cyclin-dependent kinase inhibitors, cell cycle arrest, and apoptosis. miR-101-resistant POMP restores proper turnover of proteasome substrates and re-enables tumor cell growth. In ERα-positive breast cancers, miR-101 and POMP levels are inversely correlated, and high miR-101 expression or low POMP expression associates with prolonged survival. Mechanistically, miR-101 expression or POMP knockdown attenuated estrogen-driven transcription. Finally, suppressing POMP is sufficient to overcome tumor cell resistance to the proteasome inhibitor bortezomib. Taken together, proteasome activity can not only be manipulated through drugs, but is also subject to endogenous regulation through miR-101, which targets proteasome biogenesis to control overall protein turnover and tumor cell proliferation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 07/2015; 59(2). DOI:10.1016/j.molcel.2015.05.036 · 14.02 Impact Factor
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    • "Indeed, proteasome inhibitors, bortezomib and carfilzomib, have proven effective against cancer cells in animal models and human trials by target the core proteolytic subunits PSMB5, PSMB6, and PSMB7 [11]. Now it is well established that the b4 subunit of the 20 S proteasome, PSMB4, regulates the assembly of the proteasome [12] [13]. And targeting PSMB4 could potentially prevent the catalytic activity of all three proteolytic subunits [14]. "
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    ABSTRACT: Proteasomal subunit PSMB4, was recently identified as potential cancer driver genes in several tumors. However, the regulatory mechanism of PSMB4 on carcinogenesis process remains unclear. In this study, we investigated the expression and roles of PSMB4 in multiple myeloma (MM). We found a significant up-regulation of PSMB4 in MM plasma and cell lines. Ectopic overexpression of PSMB4 promoted cell growth and colony forming ability of MM cells, whereas inhibition of PSMB4 led to a decrease of such events. Furthermore, our results demonstrated the up-regulation of miR-21 and a positive correlation between the levels of miR-21 and PSMB4 in MM. Re-expression of miR-21 markedly rescued PSMB4 knockdown-mediated suppression of cell proliferation and clone-formation. Additionally, while enforced expression of PSMB4 profoundly increased NF-κB activity and the level of miR-21, PSMB4 knockdown or NF-κB inhibition suppressed miR-21 expression in MM cells. Taken together, our results demonstrated that PSMB4 regulated MM cell growth in part by activating NF-κB-miR-21 signaling, which may represent promising targets for novel specific therapies.
    Biochemical and Biophysical Research Communications 02/2015; 458(2). DOI:10.1016/j.bbrc.2015.01.110 · 2.30 Impact Factor
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    • "ATP-dependent ubiquitin-proteasomal proteolysis is responsible for rapid and irreversible protein turnover in the cell (Finley, 2009; Pickart and Cohen, 2004). In mammals, the evolutionarily conserved proteasome contains at least 33 different protein subunits (Bedford et al., 2010; Murata et al., 2009). The 20S core particle (CP) of the proteasome is arranged into fourstacked hetero-oligomeric rings (abba) composed of seven a subunits (a1–a7) and seven b subunits (b1–b7), three of which (b1, b2, and b5) are proteolytically active subunits (Groll et al., 1997). "
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    ABSTRACT: The ubiquitin-proteasome system is a vital proteolytic pathway required for cell homeostasis. However, the turnover mechanism of the proteasome subunit itself is still not understood. Here, we show that the 20S proteasome subunit PSMA7 is subjected to ubiquitination and proteasomal degradation, which was suppressed by PSMA7 phosphorylation at Y106 mediated by the nonreceptor tyrosine kinases c-Abl/Arg. BRCA1 specifically functions as an E3 ubiquitin ligase of PSMA7 ubiquitination. c-Abl/Arg regulates cellular proteasome abundance by controlling the PSMA7 subunit supply. Downregulated PSMA7 level results in decreased proteasome abundance in c-Abl/Arg RNAi-knockdown or c-abl/arg-deficient cells, which demonstrated an increased sensitivity to proteasome inhibition. In response to oxidative stress, the c-Abl-mediated upregulation of proteasome level compensates for the proteasomal activity impairment induced by reactive oxygen species. Abl-kinases-regulated biogenesis and homeostasis of proteasome complexes may be important for understanding related diseases and pathological states. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 01/2015; 10(4). DOI:10.1016/j.celrep.2014.12.044 · 8.36 Impact Factor
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