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Determination of the operation mechanism of the proteasome, a macromolecular protein degradation enzyme, and unraveling the relationship between proteasome functional abnormalities and disease (cancer, inflammation, aging, neurodegeneration)

Research1e1.jpgFig. 1 The proteasome is able to selectively degrade proteins ubiquitinated by the ubiquitin system. It is becoming clear that selective degradation of proteins is necessary not only for removal of unnecessary proteins, but also crucial for various biological phenomena.  The proteasome is one of the intracellular protein degradation enzymes. The proteasome mainly degrades proteins tagged with an ubiquitin chain by the ubiquitin system; the ubiquitin chain serves as a degradation signal. Taken together, this system is called the ubiquitin proteasome system. The strong point of this degradation mechanism is that proteins that need to be degraded are found at pinpoint precision, and degraded at just the right time. This protein degradation system plays a central role in numerous cellular activities such as the cell cycle, signal transduction, and transcriptional control (Fig. 1).
Research1e 2.jpgFig. 2 Structure of budding yeast 26S proteasome determined by cyro-electron microscopy (Beck et al. PNAS 2012). Acidic surface charge is indicated in blue, while basic charge is indicated in red.  The proteasome is a colossal enzyme made up of a total of 33 different types of subunits, with a total of 66 subunits (Fig. 2). The proteasome is precisely and logically assembled to perform the recognition and capture of ubiquitin chains, removal of ubiquitin chains, unfolding and transport to the active center, and protein degradation all within a single proteasome (Fig. 3). However, how such a complex structure was accurately assembled remained a large mystery. To date, we have found numerous specific chaperones that assist in proteasome assembly, and revealed the detailed mechanism of proteasome assembly.
Research1e3.jpgFig. 3 The 26S proteasome is composed of two sub-complexes, the CP and RP. The RP is a regulator of the CP, and has the functions 1-4 shown in the figure. Proteins sent to the CP by the RP are degraded into peptide fragments.Furthermore, recently, we have discovered that this assembly pathway plays a pivotal role in regulating the amount of proteasomes according to the state of the cell. From the viewpoint of regulation of the amount of proteasomes, the transcriptional regulation of proteasome subunits is also largely unknown. Loss of control of proteasome amount is linked with the pathology of cancer, neurodegenerative disease, and aging. By continuing to pursue mechanisms of regulation of proteasome expression and assembly, we aim to unravel the mechanism of intracellular proteasome expression regulation and the link between proteasome levels and disease to develop novel strategies for the treatment of the above diseases.

Currently, drug development targeting the proteasome has been most effective in treating cancer. Cancer cells are known to produce abundant proteasomes for their survival, and the proteasome inhibitor bortezomib has proven highly effective against multiple myeloma. By development of “drugs that prevent increase of proteasome levels,” novel treatments for cancer could be developed.

In contrast to cancer, a decrease in proteasome function is related to aging and neurodegeneration. It is known that proteasome function decreases with age, but recent surprising reports have found that in model organisms such as D. melanogaster and C. elegans, when a decline of proteasome function was prevented, lifespan expansion and resistance to neurodegeneration were observed. This suggests that starting with neurodegeneration, a decrease in proteasome function is linked with numerous aging-associated diseases. Thus, development of “drugs that increase proteasome activity” may present novel treatments for symptoms of aging and neurodegeneration.