Proteasomes are complex protein structures within every living cell, often described as the cell’s recycling centers or quality control machinery. Their fundamental purpose involves breaking down unneeded or damaged proteins through a process called proteolysis. This degradation ensures cells remove faulty components and manage protein levels, contributing to overall cellular health and stability.
The Ubiquitin-Proteasome System
Proteasomes operate as part of a highly regulated pathway known as the Ubiquitin-Proteasome System (UPS). This system begins with a “tagging” process where proteins are marked with a small protein called ubiquitin. Ubiquitin is covalently attached to the target protein through a series of enzyme-catalyzed reactions involving ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin ligase (E3) enzymes.
Once a protein receives a single ubiquitin tag, other ligases can attach additional ubiquitin molecules, forming a polyubiquitin chain. This chain acts as a specific signal for degradation by the 26S proteasome. The proteasome itself is a multi-subunit enzyme, composed of a central, barrel-shaped 20S core particle and one or two 19S regulatory particles (regulatory caps) at each end.
The 20S core particle is a cylindrical structure made of four stacked rings, with inner rings containing the proteolytic active sites. The 19S regulatory particle recognizes polyubiquitinated proteins. It uses ATPase components to unfold the tagged protein and then translocates it into the 20S core chamber. This process yields small peptides, which can then be reused by the cell to synthesize new proteins.
Essential Cellular Functions
The precise and controlled degradation carried out by proteasomes is fundamental for maintaining a healthy cellular environment. One role involves protein quality control, where proteasomes remove misfolded or damaged proteins. This continuous clearance prevents the buildup of toxic aggregates, ensuring cellular integrity and managing protein turnover.
Proteasomes also regulate the cell cycle, the ordered series of events that lead to cell division. They do this by breaking down specific regulatory proteins, such as cyclins, at precise times. This timely degradation ensures the cell progresses through its division phases in an orderly manner, preventing uncontrolled growth or errors.
Proteasomes also contribute to the body’s immune response. When a cell is infected by a virus or encounters foreign proteins, proteasomes break these foreign proteins down into smaller peptides. These peptides are then presented on the cell surface by major histocompatibility complex (MHC) class I molecules, alerting immune cells to the presence of an invader, allowing the immune system to recognize and target infected cells.
Consequences of Proteasome Dysfunction
When the proteasome system malfunctions, various disease states can arise. In neurodegenerative disorders like Alzheimer’s, Parkinson’s, and Huntington’s diseases, impaired proteasome function is common. This leads to the accumulation of misfolded or aggregated proteins within nerve cells. For instance, in Alzheimer’s disease, reduced proteasome activity contributes to the aggregation of neurotoxic amyloid-beta and tau proteins, leading to neuronal cell death.
In Parkinson’s disease, the accumulation of alpha-synuclein and ubiquitin in Lewy Bodies reflects a failure of protein clearance. These protein aggregates can inhibit proteasome function, creating a cycle of increasing dysfunction and neuronal damage. Such aggregates disrupt cellular homeostasis, induce oxidative stress, and activate pathways leading to cell death.
Conversely, in cancer, the proteasome system is often overactive or hijacked by malignant cells. This heightened activity allows cancer cells to rapidly degrade proteins that would normally suppress tumors or trigger apoptosis. By eliminating these protective proteins, cancer cells can maintain uncontrolled growth, survive stress, and resist therapies.
Proteasomes in Modern Medicine
Understanding the proteasome’s role in disease has opened new avenues for medical interventions, particularly in cancer treatment. Proteasome inhibitors represent an advancement in this field. These drugs block proteasome action, causing an accumulation of proteins within cells.
Proteasome inhibitors are effective in treating certain cancers, such as multiple myeloma, a cancer of plasma cells. Multiple myeloma cells produce large amounts of monoclonal proteins, resulting in a high protein burden. When proteasomes are inhibited, misfolded proteins build up in the endoplasmic reticulum, triggering ER stress. This ER stress activates pro-apoptotic signals and disrupts cell cycle regulation, leading to cancer cell self-destruction.
Examples of proteasome inhibitors include bortezomib, carfilzomib, and ixazomib. Bortezomib was the first-in-class proteasome inhibitor and has improved survival rates for multiple myeloma patients. These drugs can be used alone or in combination with other therapies, offering a targeted approach to exploit cancer cell vulnerabilities.