Cathepsins are proteases, which are enzymes that are responsible for degrading proteins. There are around 12 different types of cathepsins. Each cathepsin works to degrade a different protein, and they have different structures and work via different mechanisms.
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While they contribute to the normal metabolism of cells, they also play a part in a wide range of different diseases, from diabetes to Parkinson’s disease, and cancer.
The different types of cathepsin
In mammals, proteases are grouped into five families, called metallo, serine, threonine, aspartic, and cysteine proteases. They are classified in these families based on the amino acids present in the proteins that the cathepsins break down.
All types of cathepsin are classified into three of these protease families. The serine proteases make up for up to 31% of all of the total proteases in the human body. Cysteine and aspartic proteases make up for 25% and 4% of the total proteases in the human body respectively.
The cathepsins are organized in the families shown below.
Serine family
Aspartic family
Cysteine family
- Cathepsin B
- Cathepsin C
- Cathepsin F
- Cathepsin H
- Cathepsin K
- Cathepsin L1
- Cathepsin L2
- Cathepsin O
- Cathepsin S
- Cathepsin W
- Cathepsin Z (or X)
All cathepsins are made up of a signal peptide, a propeptide, and a mature functional enzyme that is catalytically active.
The role of cathepsins in the body
Cathepsins play a role in the degradation of proteins, energy metabolism, and the body’s immune responses, among other functions.
Cathepsins are typically found in acidic endocytic or lysosomal systems, but some cathepsins function above the optimal pH 5 level, namely cathepsin S, which is active at pH 6.5. Cathepsin D is usually most active at pH 4, but it has also been found that cathepsin D is active at higher pH levels up to pH 7.4.
Almost all cathepsin activity is found in lysosome organelles, which are a type of organelle responsible for breaking down excess or aging parts of cells and in aiding apoptosis (cell death). Lysosomes can also destroy viruses and bacteria.
Cathepsins break down proteins by cutting the peptide bonds that link amino acids together.
Cathepsins in disease
Cathepsins play important roles in the endosomes of immune cells and are active in innate and adaptive immune responses. Certain studies have concluded that if the body’s pH level is too low, also known as acidosis, cathepsins can begin to cause problems and lead to the development of disease.
Dysregulated cathepsin synthesis and activity have been seen in several diseases, rheumatoid arthritis, cancer, and inflammatory neurological diseases. As they can affect a huge range of different types of diseases, they are often of particular interest in the study of disease progression, as well as disease prevention.
Dysregulated cathepsin activity can result in the overexpression (over-activity) of the cathepsins and cause them to be secreted outside of cells. This can cause problems in the extracellular matrix (ECM), which is the non-cellular part of all tissues and organs and helps cells behave normally during cell proliferation, cell differentiation, and cell migration.
When in the extracellular matrix, cysteine cathepsins, in particular, can degrade the structural components of the ECM, such as collagen or elastin, and contribute to the processing of chemokines, which are molecules that are involved in activating inflammatory immune responses. As such, extracellular cysteine cathepsins may be implicated in certain inflammatory diseases such as arthritis or psoriasis and could be important in studying treatments for these types of diseases.
Neurodegenerative diseases
Cathepsins are important in neurodegenerative diseases as they break down several important proteins. Huntington’s and Parkinson’s disease has been linked to cathepsin D, which plays a part in the homeostasis of neuronal cells. When this homeostasis is impaired, the proteolysis of particular proteins is impaired. These proteins include:
- Huntingtin
- Tau
- Lipofuscin
- apoE
- α-synuclein.
Cardiovascular diseases
The types of cardiovascular diseases that may be influenced by cathepsin activity include:
- Cardiomyopathy (diseases of heart muscle)
- Hypertension (high blood pressure)
- Myocardial infarction (heart attack)
- Atherosclerosis (buildup of fats and cholesterol in the arteries)
- Aortic aneurysms (swelling in the blood vessel from the heart to the stomach).
These diseases may also involve the degradation of the extracellular matrix by cathepsins. For instance, cathepsins have been found to degrade low-density lipoprotein (LDL-P) and reduce the effect of cholesterol leaving macrophages. This leads to foam cells being created, which have been linked to atherosclerosis and coronary artery disease specifically.
Cancer
Cathepsins are involved in growth, invasion, angiogenesis (the development of new blood vessels), and tumors becoming resistant to medication. Degradation of the extracellular matrix has also been found to play a part in metastatic cancer, which is when cancer moves from its primary site, such as the lungs, to another part of the body, such as the bones. This means that cathepsin dysfunction that leads to ECM degradation may help cancer spread to secondary parts of the body.
Metabolic disorders
Obesity and diabetes both potentially involve cathepsins L, S, H, and K. Cathepsin H may lead to diabetes through endopeptidase activity when it becomes dysregulated. Cathepsin K can contribute to obesity by breaking down collagen proteins in the ECM.
Other diseases that are linked to cathepsin dysregulation include:
- Periodontitis
- Pancreatitis
- Macular degeneration
- Muscular dystrophy
- Stroke
- Schizophrenia
- Tuberculosis
- Ebola.
Cathepsin inhibitors can stop cathepsin function, which can stop tumors from forming through blocking angiogenesis. Cathepsin inhibitors can also reduce how well tumor cells can move around the body and how invasive they are.
Summary
Cathepsins are a vital part of the human body, but imbalances in the body’s pH level and other serious problems such as hypoxia can cause cathepsins to become dysregulated, which can, in turn, lead to disease.
Cathepsins play important roles in several common diseases, and as such, they are the focus of study into disease prevention and progression. Understanding the role of cathepsins in disease can help to develop effective therapies for serious pathologies such as cancer and Alzheimer’s, but overall, there is still a lack of understanding on how cathepsins work inside the body, and how they influence disease.
References
Further Reading
The crucial role of 'chaperones' in maintaining neuronal function