Monomeric ubiquitin is relatively stable; however, it appears to be degraded by the proteasome following its own ubiquitylation, which is mediated by the thyroid receptor-interacting protein 12 (TRIP12) ligase. Ubiquitin is also degraded through two other mechanisms: along with the target substrate as part of the polyubiquitin chain attached to it, and along with a peptide attached, either linearly or in an isopeptide bond, to its carboxy-terminal Gly residue.
Ubiquitin-protein ligases (E3s) are largely responsible for conferring substrate specificity to the ubiquitin–proteasome system (UPS). An increasing number of these ligases are being shown to be subject to self-ubiquitylation (also known as auto-ubiquitylation), ubiquitylation by heterologous ligases, or both. In some cases, both self-ubiquitylation and ubiquitylation by heterologous ligases lead to degradation of the protein. In other cases, self-ubiquitylation can regulate the cellular function of the ligase, whereas ubiquitylation by a heterologous E3 results in degradation of the target ligase.
Other components of the UPS, including ubiquitin-conjugating enzymes (E2s) and deubiquitylating enzymes, are also subject to ubiquitylation.
Components of the ubiquitin system are also subject to modification by other ubiquitin-like protein modifiers.
The 26S proteasome is a stable, long-lived complex and is probably degraded through microautophagy. As part of the response to some specific cellular signals, such as oxidative stress, starvation, and stimulation of the NMDA (N-methyl-D-aspartate) receptor, it is disassembled into its two subcomplexes, the 19S regulatory particle (RP) and the 20S catalytic (or core) particle (CP). The RP is probably disassembled into its individual subunits, which are degraded by the proteasome following ubiquitylation. Caspase-mediated cleavage of specific 19S subunits has also been shown to regulate proteasomal activity under certain conditions.
The effect of disassembly of the 26S proteasome on the 20S complex has remained unclear: in some cases it was shown to inhibit its activity, to avoid damage of uncontrolled degradation, whereas in others cases it has been shown to stimulate activity and to efficiently remove — apparently in a ubiquitin-independent manner — excess damaged proteins.
Ubiquitylation (also known as ubiquitination) regulates essentially all of the intracellular processes in eukaryotes through highly specific modification of numerous cellular proteins, which is often tightly regulated in a spatial and temporal manner. Although most often associated with proteasomal degradation, ubiquitylation frequently serves non-proteolytic functions. In light of its central roles in cellular regulation, it has not been surprising to find that many of the components of the ubiquitin system itself are regulated by ubiquitylation. This observation has broad implications for pathophysiology.
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Space constrains do not allow us to cite many of the studies in this evolving, yet already prolific, research area, and we apologize for that. Research in the laboratory of A.M.W. is supported by the US National Institutes of Health National Cancer Institute and Center for Cancer Research. Research in the laboratory of A.C. is supported by grants from the Miriam and Sheldon Adelson Foundation for Medical Research, the Israel Science Foundation, the German–Israeli Foundation for Research and Scientific Development, the Deutsch–Israelische Projektkooperation and Rubicon — the European Union Network of Excellence Studying the Role of Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation. A.C. is an Israel Cancer Research Fund USA Professor.
The authors declare no competing financial interests.
- Deubiquitylating enzymes
(DUBs; also known as deubiquitinating enzymes and ubiquitin-specific proteases). These enzymes have multiple roles, for example, in processing ubiquitin precursors, in disassembling and trimming ubiquitin chains and in antagonizing the activity of ubiquitin-protein ligases in general or towards specific substrates.
- Catalytic particle
(CP). The 20S core particle of the 26S proteasome. It is made of four rings: two external α-rings that are each made of seven distinct subunits (which are identical between the rings), and two adjacent β-rings, also made of seven distinct subunits (which are also identical between the rings). Three of the seven β-subunits are proteases with distinct cleaving activities.
- 'Canonical' ubiquitin chains
Lys48-based chains that are well-characterized as being proteasome targeting signals.
- Regulatory particle
(RP). The 19S complex of the 26S proteasome, which consists of two subcomplexes that are linked together — the base and the lid. The base contains the ATPases that are involved in unfolding the substrate and in opening the entrance to the catalytic 20S subcomplex. The lid contains the polyubiquitin chain-recognizing subunits. The RP also includes deubiquitylating enzymes that recycle ubiquitin.
- Helper T cells
T cells that function as inducers of the effector cells for humoral and cell-mediated immunity. These cells recognize and bind antigens.
- Unfolded protein response
(UPR). A cellular response that is triggered by the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and that results in the transcriptional upregulation of ER chaperones and degradative enzymes and a general inhibition of protein synthesis.
The formation of vacuoles containing a small portion of the cytosol that is digested by the lysosomal enzymes following the destruction or dissolution of the surrounding membrane. The process occurs under basal metabolic conditions and, unlike stress-induced macroautophagy, the vacuoles are small and their generation does not involve the formation of a new membrane and the engulfment and digestion of membrane-limited organelles.
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Weissman, A., Shabek, N. & Ciechanover, A. The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation. Nat Rev Mol Cell Biol 12, 605–620 (2011). https://doi.org/10.1038/nrm3173
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