Cathepsins are a family of enzymes that act like biological scissors, breaking down proteins. These enzymes are fundamental to many essential biological processes, maintaining the health and function of cells and tissues. Their activity is crucial for the continuous renewal and repair within the body.
What Are Cathepsins?
Cathepsins are a group of proteolytic enzymes. There are approximately a dozen different members in this family, each distinguished by the specific proteins it targets for cleavage. These enzymes are broadly categorized based on their active site mechanism, falling into three main classes: cysteine cathepsins (e.g., Cathepsin B, L, K, S), aspartic cathepsins (e.g., Cathepsin D, E), and serine cathepsins (e.g., Cathepsin A, G).
Most cathepsins are primarily located within lysosomes, which are cellular compartments responsible for waste disposal and recycling. The highly acidic environment inside lysosomes is essential for the activation and optimal function of these enzymes. However, some cathepsins can also function outside lysosomes, such as cathepsin K, which can work extracellularly in specific processes like bone resorption, and cathepsin S and D, which can be active at less acidic or even neutral pH levels.
Physiological Roles
Cathepsins play diverse and essential roles in maintaining the body’s normal functions, participating in processes that are fundamental for cellular health and systemic balance. Their activity is crucial for the continuous breakdown and recycling of cellular proteins and organelles, a process known as protein turnover, which is vital for cell health and adaptation. This constant renewal helps cells remove damaged components and adapt to changing conditions.
In the immune system, cathepsins are involved in antigen presentation, a process where immune cells display fragments of foreign proteins (antigens) to trigger an immune response. Cathepsin S, for instance, is crucial for processing the invariant chain, which is necessary for the proper presentation of antigens by MHC class II molecules to T cells, thereby enabling effective adaptive immunity. Cathepsin G also contributes to antigen presentation and immune regulation by modifying chemokines and cytokines.
Certain cathepsins have specific functions in tissue remodeling, such as cathepsin K, which is highly expressed by osteoclasts, the cells responsible for breaking down bone tissue. Cathepsin K is the most potent mammalian collagenase, meaning it efficiently degrades collagen, a major component of bone’s non-mineral protein matrix, thereby playing a central role in bone resorption and remodeling. This process is important for bone growth, repair, and maintaining bone density.
Cathepsins in Disease
While cathepsins are essential for health, their dysregulation can contribute to various disease states. In cancer, certain cathepsins can promote tumor growth, invasion, and the spread of cancer cells (metastasis). For example, cathepsins B, K, L, and S can degrade components of the extracellular matrix, which is the network of proteins and other molecules surrounding cells, thereby facilitating the movement of cancer cells through tissues. Elevated levels of cathepsin D in tumor cells have been associated with greater invasiveness, and high levels of cathepsin B are linked to increased metastasis in lung cancer.
In neurodegenerative diseases like Alzheimer’s and Parkinson’s, cathepsins are implicated due to their role in lysosomal function and protein aggregation. Lysosomes are responsible for clearing misfolded proteins, and when their function is impaired, protein aggregates can accumulate, contributing to disease progression. Research suggests that elevated cathepsin H levels may increase the risk of Alzheimer’s disease, while cathepsin B might have a protective effect against Parkinson’s disease by helping to clear alpha-synuclein, a protein that forms aggregates in this condition. Cathepsin D is also involved in degrading misfolded proteins, including those found in Parkinson’s and Alzheimer’s disease.
Cathepsins also contribute to chronic inflammatory and autoimmune conditions, where the immune system mistakenly attacks the body’s own tissues. For instance, cathepsin S, released from tissue macrophages, contributes to extracellular matrix degradation in conditions such as atherosclerosis, arthritis, and chronic obstructive pulmonary disease. Cathepsin G also plays a role in inflammation and immune reactions, with increased concentration and activity found in the synovial fluid of rheumatoid arthritis patients.
Emerging evidence points to roles for cathepsins in cardiovascular diseases, including atherosclerosis and heart failure. Cysteine cathepsins like cathepsin S and B are abundant in the heart muscle of patients with hypertensive heart failure, suggesting their involvement in the turnover of the extracellular matrix and cardiac remodeling in these conditions.
Regulation of Cathepsin Activity
The body employs several mechanisms to control cathepsin activity and prevent unintended damage to healthy tissues. One important regulatory factor is pH dependence. Most cathepsins are optimally active in the acidic environment of lysosomes. If cathepsins escape into the neutral pH of the cell’s main compartment (cytosol) or the extracellular space, their activity is significantly reduced, limiting their ability to cause widespread damage.
The body also produces endogenous inhibitors, which are specific proteins that bind to and inactivate cathepsins. For example, cystatins are a family of protein inhibitors that specifically target and inhibit cysteine cathepsins, acting as a crucial brake on their activity.
Another layer of control comes from the compartmentalization of cathepsins. Their primary confinement within lysosomes helps to localize their proteolytic activity to specific cellular compartments, preventing them from indiscriminately degrading proteins throughout the cell. Even when secreted and active outside lysosomes, their functions in these extralysosomal locations are tightly regulated to prevent pathological outcomes.