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 is an enzymatic mega complex composed of at least 33 different subunits, assembled into two parts—a highly conserved, catalytic 20S core particle and one or two 19S regulatory particles. These particles assemble independently with the help of cytoplasmic chaperones before forming the 26S proteasome complex (Coux et al., 1996; Murata et al., 2009). Recent studies indicate that UPS contributes to axon growth and guidance (Campbell and Holt, 2001). "
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    ABSTRACT: Axon extension at the growing tip requires elevated local protein supply, with a capability sustainable over long axons in varying environments. The exact mechanisms, however, remain elusive. Here we report that axon-promoting factors elicited a retrograde transport-dependent removal of proteasomes from nascent axon terminals, thereby increasing protein stability at axon tips. Such an effect occurred through phosphorylation of a dynein-interacting proteasome adaptor protein Ecm29. During the transition from immature neurites to nascent axons in cultured hippocampal neurons, live-cell imaging revealed a significant increase of the retrograde axonal transport of fluorescently labeled 20S proteasomes. This retrograde proteasome transport depended on neuron stage and increased with axon lengths. Blockade of retrograde transport caused accumulation of proteasomes, reduction of axon growth, and attenuation of growth-associated Par6 at the axon tip of newly polarized neurons. Our results delineate a regulatory mechanism that controls proteasome abundance via preferential transport required for axon development in newborn neurons.
    Developmental Cell 11/2015; 35(4):418-431. DOI:10.1016/j.devcel.2015.10.018 · 9.71 Impact Factor
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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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