Proteasomes are large supramolecular protein complexes present in all prokaryotic and eukaryotic cells, where they perform targeted degradation of intracellular proteins. Until recently, it was generally accepted that prior proteolytic degradation in proteasomes the proteins had to be targeted by ubiquitination: the ATP-dependent addition of (typically four sequential) residues of the low-molecular ubiquitin protein, involving the ubiquitin-activating enzyme, ubiquitin-conjugating enzyme and ubiquitin ligase. The cytoplasm and nucleoplasm proteins labeled in this way are then digested in 26S proteasomes. However, in recent years it has become increasingly clear that using this route the cell eliminates only a part of unwanted proteins. Many proteins can be cleaved by the 20S proteasome in an ATP-independent manner and without previous ubiquitination. Ubiquitin-independent protein degradation in proteasomes is a relatively new area of studies of the role of the ubiquitin-proteasome system. However, recent data obtained in this direction already correct existing concepts about proteasomal degradation of proteins and its regulation. Ubiquitin-independent proteasome degradation needs the main structural precondition in proteins: the presence of unstructured regions in the amino acid sequences that provide interaction with the proteasome. Taking into consideration that in humans almost half of all genes encode proteins that contain a certain proportion of intrinsically disordered regions, it appears that the list of proteins undergoing ubiquitin-independent degradation will demonstrate further increase. Since 26S of proteasomes account for only 30% of the total proteasome content in mammalian cells, most of the proteasomes exist in the form of 20S complexes. The latter suggests that ubiquitin-independent proteolysis performed by the 20S proteasome is a natural process of removing damaged proteins from the cell and maintaining a constant level of intrinsically disordered proteins. In this case, the functional overload of proteasomes in aging and/or other types of pathological processes, if it is not accompanied by triggering more radical mechanisms for the elimination of damaged proteins, organelles and whole cells, has the most serious consequences for the whole organism.
Proteasomy – slozhno organizovannye mul'tifermentnye kompleksy, prisutstvuiushchie vo vsekh prokarioticheskikh i éukarioticheskikh kletkakh, – osushchestvliaiut targetnuiu degradatsiiu vnutrikletochnykh belkov. Do poslednego vremeni schitalos' obshchepriniatym, chto popadaniiu podlezhashchikh proteasomnoĭ degradatsii belkov v proteasomu predshestvuet ikh ubikvitinirovanie: ATR-zavisimoe prisoedinenie (kak pravilo, posledovatel'no chetyrekh) ostatkov nizkomolekuliarnogo belka ubikvitina, v kotorom uchastvuiut ubikvitin-aktiviruiushchiĭ ferment, ubikvitin- kon"iugiruiushchiĭ ferment i ubikvitinligaza. Mechennye takim obrazom belki tsitoplazmy i nukleoplazmy zatem podvergaiutsia rasshchepleniiu v 26S proteasomakh. Odnako v poslednie gody stanovitsia vse bolee ochevidnym, chto takim obrazom kletka izbavliaetsia lish' ot chasti nezhelatel'nykh belkov. Mnogie belki mogut rasshchepliat'sia 20S proteasomoĭ ATR-nezavisimym sposobom i bez predvaritel'nogo ubikvitinirovaniia. Ubikvitin-nezavisimaia degradatsiia belkov v proteasomakh – otnositel'no novoe napravlenie issledovaniĭ roli ubikvitin-proteasomnoĭ sistemy, kotoroe uzhe seĭchas vnosit svoi korrektivy v sushchestvuiushchie predstavleniia o proteasomnoĭ degradatsii belkov i ee reguliatsii. Odnoĭ iz osnovnykh strukturnykh predposylok ubikvitin-nezavisimoĭ proteasomnoĭ degradatsii iavliaetsia nalichie nestrukturirovannykh oblasteĭ v aminokislotnykh posledovatel'nostiakh belkov, kotorye i obespechivaiut vzaimodeĭstvie s proteasomoĭ. S uchetom togo, chto u cheloveka pochti polovina vsekh genov kodiruet belki, soderzhashchie opredelennyĭ protsent neuporiadochennykh uchastkov, mozhno ozhidat', chto so vremenem kolichestvo belkov, dlia kotorykh pokazana ubikvitin-nezavisimaia degradatsiia, budet rasti. Poskol'ku na doliu 26S proteasom prikhoditsia vsego 30%, a v kletkakh mlekopitaiushchikh bol'shaia chast' proteasom nakhoditsia v vide 20S kompleksov, ochevidno, chto ubikvitin-nezavisimyĭ proteoliz, osushchestvliaemyĭ 20S proteasomoĭ, predstavliaet soboĭ zakonomernyĭ protsess udaleniia iz kletki povrezhdennykh belkov i podderzhaniia postoiannogo urovnia vnutrenne neuporiadochennykh belkov. Pri étom funktsional'naia peregruzka étikh chastits pri starenii i/ili drugikh vidakh patologicheskikh protsessov, esli ona ne soprovozhdaetsia vkliucheniem bolee radikal'nykh mekhanizmov éliminatsii povrezhdennykh belkov, organell i tselykh kletok, imeet samye ser'eznye posledstviia dlia vsego organizma.
Keywords: proteasome; ubiquitin-independent protein degradation; ubiquitin-proteasome protein degradation system.