Proteasomes are intricate cellular machines responsible for breaking down unwanted or damaged proteins within living cells. This process, known as proteolysis, converts large proteins into smaller peptides or amino acids for recycling. Present in all eukaryotic cells, they are fundamental for maintaining cellular health and balance.
Thousands of these barrel-shaped structures reside in the cytoplasm and nucleus of a typical body cell. Their continuous activity ensures cellular environments remain free of harmful protein accumulation, which can disrupt normal cell functions and lead to various health problems. The precise and regulated action of proteasomes is a constant requirement for cellular vitality.
How Proteasomes Dismantle Proteins
Proteasomes primarily degrade proteins using the ubiquitin-proteasome system (UPS). Proteins are first marked with a small protein called ubiquitin. This tagging, ubiquitination, is a multi-step enzymatic cascade involving three main types of enzymes: E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase).
The E1 enzyme activates ubiquitin in an ATP-dependent manner, after which it is transferred to an E2 enzyme. The E2 enzyme, in conjunction with an E3 ligase, then facilitates the attachment of ubiquitin to specific lysine residues on the target protein. This often leads to the formation of a polyubiquitin chain, typically consisting of at least four ubiquitin molecules, which serves as a signal for proteasomal degradation.
Once a protein is marked with a polyubiquitin chain, the 26S proteasome recognizes this tag. The 26S proteasome is a large complex composed of a barrel-shaped 20S core particle and one or two 19S regulatory particles. The 19S regulatory particle binds to the ubiquitinated protein, unfolds it in an ATP-dependent process, and then threads it into the central chamber of the 20S core.
Inside the 20S core, catalytic subunits, specifically beta subunits, break down the unfolded protein into short peptides, typically 7-9 amino acids in length. These peptides are then released into the cytosol, where they can be further broken down into individual amino acids by other enzymes or presented on the cell surface for immune surveillance. The ubiquitin molecules are also recycled for reuse.
Essential Roles of Proteasomes in Cells
Beyond waste disposal, proteasomes carry out numerous functions integral to cellular regulation and maintenance. They regulate the cell cycle by controlling the progression of cell division. By precisely degrading specific regulatory proteins, such as cyclins, proteasomes ensure that cells move through their growth and division phases in an orderly manner.
Proteasomes also regulate gene expression by controlling transcription factors and other proteins involved in gene activation and deactivation. This precise control over protein abundance allows cells to respond to internal and external signals by turning specific genes on or off as needed. This contributes to a cell’s ability to adapt and specialize.
The immune response also relies on proteasome activity, particularly for antigen presentation. Specialized proteasomes, known as immunoproteasomes, are found in immune cells and are induced by inflammatory signals like interferon-gamma. These variants produce peptides that are presented on major histocompatibility complex (MHC) class I molecules, allowing the immune system to identify and respond to infected or abnormal cells.
Cells utilize proteasomes in stress response. When cells encounter various stresses, such as oxidative damage or heat, proteins can become misfolded or damaged. Proteasomes efficiently clear these abnormal proteins, preventing their toxic accumulation and helping the cell cope with adverse conditions. This removal of misfolded proteins is a fundamental aspect of protein quality control.
Maintaining protein homeostasis, also known as proteostasis, is another function of proteasomes. This involves a dynamic balance between protein synthesis, folding, and degradation. By selectively degrading misfolded or unneeded proteins, proteasomes prevent the buildup of potentially toxic aggregates and ensure that protein levels are regulated appropriately for cellular functions.
Proteasome Dysfunction and Health
When proteasome function is impaired, either by being overactive or underactive, it can have serious consequences for cellular health and contribute to various diseases. Neurodegenerative diseases are a significant area affected by proteasome dysfunction, where the accumulation of misfolded or aggregated proteins is a common feature. In conditions like Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, insufficient proteasome activity can lead to the buildup of specific toxic proteins, such as alpha-synuclein or polyglutamine proteins, which disrupt neuronal function and eventually lead to cell death.
Research indicates that deposits of ubiquitinated proteins are found in affected neurons in these disorders, suggesting that the proteasome system is overwhelmed or compromised. While some studies show decreased proteasome activity in postmortem tissues from individuals with neurodegenerative diseases, other findings suggest that activity might be unchanged or even increased as an adaptive response to the high load of misfolded proteins. Modulating proteasome function, perhaps through activation, is being explored as a therapeutic strategy.
Cancer development can also be linked to proteasome activity. Overactive proteasomes can contribute to uncontrolled cell growth by rapidly degrading tumor suppressor proteins, which normally help regulate cell division. This accelerated breakdown removes natural brakes on cell proliferation, allowing cancer cells to multiply unchecked.
Conversely, inhibiting proteasome activity has become a successful therapeutic strategy in certain cancers, particularly multiple myeloma. Drugs like bortezomib, a proteasome inhibitor, work by preventing the degradation of proteins that would otherwise trigger cell death in cancer cells, thus inducing their demise. This approach highlights how targeting proteasome function can be used to selectively eliminate malignant cells.
Dysregulated proteasome activity can also contribute to immune disorders and chronic inflammation. Alterations in the ubiquitin-proteasome system can lead to abnormal inflammatory responses. The precise control of immune signaling depends on the balanced degradation of regulatory proteins by proteasomes, and any imbalance can result in the immune system attacking its own tissues or remaining chronically activated.