Ubiquitin-Proteasome System in Cellular Regulation

The ubiquitin–proteasome system is the principal pathway for targeted protein degradation in eukaryotic cells, governing proteostasis and controlling key processes such as cell cycle progression, signal transduction, transcriptional regulation and stress responses. Proteins destined for destruction are tagged by chains of the small protein ubiquitin through the coordinated action of activating (E1), conjugating (E2) and ligase (E3) enzymes. Polyubiquitylated substrates are recognised by the 19S regulatory particle, which unfolds and translocates them into the 20S core, completing degradation in the 26S holoenzyme. In parallel, the 20S proteasome can degrade intrinsically disordered or damaged proteins without ubiquitylation. Specialised variants, such as the immunoproteasome, tailor peptide generation for antigen presentation. Fine-tuning of these pathways ensures cellular adaptation to oxidative stress, nutrient availability and infection, while dysregulation underlies neurodegenerative disorders, cancer and inflammatory diseases. Pharmacological modulation of proteasome activity has yielded effective therapies in oncology, and emerging strategies aim to develop selective inhibitors or activators to restore homeostasis in diverse pathological settings.

Research from Nature Portfolio

Allosteric control of the uncapped 20S proteasome by a newly characterised family of Catalytic Core Regulators (CCRs) has revealed a mechanism by which binding to the non-catalytic PSMB4 subunit attenuates all three proteolytic activities. Structural dissection of CCR-like motifs enabled design of a minimal synthetic regulator, opening avenues to decouple 20S- and 26S-mediated degradation and to develop selective 20S inhibitors. In a complementary study, a unifying conformational motif in misfolded oligomers associated with Alzheimer’s, Parkinson’s and Huntington’s diseases was shown to allosterically lock the 20S gate in a closed state. This blockade prevents entry of both ubiquitin-dependent and ‑independent substrates, providing a molecular basis for proteasome impairment in neurodegeneration and highlighting novel targets to restore proteolytic capacity in affected neurons.

Ubiquitin-Proteasome System in Cellular Regulation publication trend

The graph below shows the total number of articles in ubiquitin-proteasome system in cellular regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Ubiquitin: A small regulatory protein that is covalently attached to substrates to mark them for proteasomal degradation.

Ubiquitylation: The enzymatic process of conjugating ubiquitin molecules to a target protein, often forming a chain that signals degradation.

26S proteasome: A 2.5 MDa protease complex comprising a 20S core and one or two 19S regulatory particles, responsible for ATP-dependent degradation of ubiquitylated proteins.

20S proteasome: The proteolytic chamber of the proteasome capable of degrading unfolded or intrinsically disordered proteins independently of ubiquitin tagging.

Immunoproteasome: A specialised proteasome variant induced by inflammatory cytokines, optimised for rapid generation of antigenic peptides.

Proteasome inhibitor: A molecule that binds to and blocks proteasomal proteolytic sites, used experimentally and clinically to modulate protein turnover.

Pyroptosis: A form of programmed cell death characterised by caspase-3 or gasdermin activation, leading to inflammatory membrane rupture.

References

1. Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family. Nature Communications (2023).
2. A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nature Communications (2018).
3. Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases. Signal Transduction and Targeted Therapy (2024).
4. Immunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia. Molecular Cancer (2023).