Degradation of oxidized proteins by the proteasome: Distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways

Abstract

The proteasome is a ubiquitous and highly plastic multi-subunit protease with multi-catalytic activity that is conserved in all eukaryotes. The most widely known function of the proteasome is protein degradation through the 26S ubiquitin-proteasome system, responsible for the vast majority of protein degradation during homeostasis. However, the proteasome also plays an important role in adaptive immune responses and adaptation to oxidative stress. The unbound 20S proteasome, the core common to all proteasome conformations, is the main protease responsible for degrading oxidized proteins. During periods of acute stress, the 19S regulatory cap of the 26S proteasome disassociates from the proteolytic core, allowing for immediate ATP/ubiquitin-independent protein degradation by the 20S proteasome. Despite the abundance of unbound 20S proteasome compared to other proteasomal conformations, many publications fail to distinguish between the two proteolytic systems and often regard the 26S proteasome as the dominant protease. Further confounding the issue are the differential roles these two proteolytic systems have in adaptation and aging. In this review, we will summarize the increasing evidence that the 20S core proteasome constitutes the major conformation of the proteasome system and that it is far from a latent protease requiring activation by binding regulators.

Oxidised protein metabolism: recent insights

“…As the focus of this minireview is on recent insights, these proteolytic pathways will only be briefly reviewed and more detailed reviews can be found elsewhere (Pickering and Davies, 2012;Settembre et al, 2013;Chondrogianni et al, 2014;Raynes et al, 2016). Natively folded proteins can be efficiently reversed by enzymes such as thioltransferases and methionine sulfoxide reductases.…”

Ubiquitin-independent protein degradation in proteasomes

“…Однако в последнее время гипотеза о том, что протеасомы в клетке существуют в основном в виде 20S-комплексов и во многих случаях играют решающую роль в убиквитин-независимой деградации белков (например, в условиях окислительного стресса, при старении и развитии ряда сердечно-сосудистых и нейродегенеративных заболеваний) [31], получает всё большее подтверждение.…”

“…Деградации непосредственно 20S протеасомой подвергаются белки, содержащие неструктурированные области, появившиеся в результате окисления, мутации или старения [27][28][29][30][31][32]. Подобное расщепление характерно и для так называемых внутренне неупорядоченных белков, то есть нативных белков, содержащих неупорядоченные участки (partly-folded proteins) [33] (44)убиквитин-независимое расщепление.…”

“…Для ряда белков было показано, что окислительный стресс способствует переключению убиквитин-зависимой деградации белков 26S протеасомой на убиквитин-и АТР-независимое расщепление белков 20S протеасомой с присоединённым к ней регулятором PA28g (или REGg). В частности, такой механизм работает в случае супрессора опухолей р21 и корового белка гепатита С. Протеасомная деградация окисленных белков подробно описана в обзоре [31].…”

Chlorocarbonylsulfenyl Chloride Cyclizations Towards Piperidin-3-yl-oxathiazol-2-ones as Potential Covalent Inhibitors of Threonine Proteases

“…7 Immunoproteasome is also important for the generation of peptides for antigen presentation; moreover, recent studies also suggest a pleiotropic role in cellular function of the immunoproteasome. [8][9][10] There is an amounting body of research on the small-molecule inhibitors of proteasomes. 5,11 Both marketed medicines, bortezomib and carfilzomib, equally inhibit the catalytically active β5 subunits of the constitutive proteasome and the immunoproteasome.…”