Cathepsins: Lysosomal Proteases that are Vital and Lethal

Hari Krishnan R, SRM Institute of Science and Technology

Proteases are enzymes that break down proteins and perform very important functions in the body, including digestion, reducing inflammation. Cathepsins (CTS) are a group of lysosomal proteases that are found in almost all organisms and are essential for the normal metabolism of the body but also play a role in a wide variety of diseases. There are around 15 types of cathepsins that have serine, cysteine, or aspartic acid as their nucleophile and are highly functional under low pH found in lysosomes.

Localized in lysosomes they play a vital role in digestion, peptide synthesis, immunity, coagulation, and hormone secretion. Once released from the lysosomes they degrade collagen and elastin in the extracellular matrix that leads to infections, tumor metastasis, autoimmune disorders, and cardiovascular and neural diseases. 

Classification of Cathepsins

Cathepsins are categorized into multiple classes based on the structure, catalytic activity, and nucleophile residues. 

1. Serine Proteases – The serine protease class of cathepsin includes Cathepsin A and Cathepsin G. 
2. Aspartyl Proteases- They have aspartic acid as their nucleophilic residue and include Cathepsin D and Cathepsin E.
3. Cysteine Protease- The largest class of cathepsin proteases includes, Cathepsin B, C, F, H, K, L1, L2, O, S, W and, Z.

Few Cathepsins are found throughout the body (B, H, X, O, C and L) whereas few Cathepsins are tissue-specific. For eg- Macrophages express Cathepsin F, Cathepsin K is found in osteoblasts and involved in bone-related disorders. Cathepsin S, V and, W are found in immune cells like Antigen-presenting cells, T-cells, Natural Killer cells, and Cytotoxic cells.

Cathepsin Associated Diseases

• Cathepsin A serine protease is encoded by the CTSA gene which when mutated causes a rare condition called galactosialidosis. This condition is caused by a deficiency of neuraminidase and beta-galactosidase.
• Cathepsin B cysteine protease is a beta-secretase enzyme that cleaves amyloid precursor protein to form amyloid-beta. Amyloid-beta plaques accumulation is a marker for Alzheimer’s disease. Cathepsin B is encoded by the CTSB gene whose overexpression is associated with oesophageal and ovarian cancer.
• Cathepsin C cysteine protease is encoded by the CTSC gene. Mutation or defects in this gene is associated with an autosomal recessive disorder called Papillon-Lefevre Disease characterized by abnormal keratosis and periodontitis.
• Cathepsin D is an aspartyl protease encoded by the CTSD gene. Cathepsin D is a mitogen that inhibits the function of dendritic cells in breast cancer. It is also associated with neuronal ceroid lipofuscinosis (NCL), which is a lysosomal storage disease caused by excess accumulation of lipofuscin.
• Encoded by the CTSE gene, Cathepsin E is an aspartyl protease whose deficiency is associated with atopic dermatitis. 
• Cysteine protease Cathepsin F is encoded by the CTSF gene whose mutation is linked to Type B Kufs disease which is a type of NCL. Overexpression of Cathepsin H, encoded by the CTSH gene is linked to prostate cancer malignancies.
• Encoded by the CTSK gene, Cathepsin K is the most potent collagen-cleaving enzyme (collagenase). Expression of this is linked to various disorders including, Osteoporosis, Arthritis, Obesity, and many more.
• Cathepsin L1 encoded by CSTL1 gene is associated with myofibril necrosis and Cathepsin L2 also known as Cathepsin V encoded by CTSV gene is associated with various hyperplasia.
• Cathepsin O encoded by the CTSO gene is a collagenase involved in various cardiovascular disorders. 
• Cathepsin S encoded by the CTSS gene is upregulated in psoriasis and sclerosis. It is known to cleave a variety of ECM proteins.
• Encoded by the CTSW gene, cathepsin W expression is associated with inflammatory bowel disease. 
• Cysteine protease Cathepsin Z (or P/X) is associated with tumorigenesis and malignancies.

Inhibitors of Cathepsins

As Cathepsins are implicated in several diseases, their inhibition can act as a potential therapeutic strategy in various chronic diseases like cancer, arthritis, and few viral diseases like Ebola and SARS. There are numerous inhibitors of Cathepsins, many of which are of natural origin. These natural origin inhibitors are extracted from bacteria, fungus, and plants. Bifalvones extracted from plants inhibit Cathepsin B and K. Gallinamide A which is a marine cyanobacterial metabolite that inhibits Cathepsin L. Few amino acid derivatives inhibit Cathepsin A. Aspergillus extract inhibits Cathepsin B.

Few other Cathepsin inhibitors include Pepstatin A which is an inhibitor of Cathepsin D and E. Phenylmethylsulfonyl fluoride (PMSF) and 4-benzenesulfonyl fluoride hydrochloride (AEBSF) are synthetic inhibitors of serine proteases (Cathepsin A and G). Few other serine protease inhibitors are antithrombin and alpha-1-antitrypsin (A1AT).

Role of Cathepsin L in COVID-19

COVID-19 pandemic has been one of the most devastating pandemics in the history of mankind. Researchers worldwide are still working on an effective solution to fight the disease by understanding their dynamics and identifying therapeutic targets. Cathepsin L encoded by the CSTL gene is usually a matrix-degrading cysteine protease associated with chronic inflammation. A recent study has identified that inflammation caused due to the over-expression of Cathepsin L helps SARS-CoV2 to enter into host cells. The virus enters the cell through endocytosis in an endosome, where Cathepsin L mediates cleavage of spike protein for its activation and further stages of infection. This role of Cathepsin L has made it a potential therapeutic target for COVID-19 treatment.

Currently, researchers are focusing on Cathepsin L inhibitors few of which include beta-lactams, epoxy succinic acid, vinyl sulfone, and acyl hydrazine. Chloroquine and hydroxychloroquine which are usually prescribed for malaria are also been considered as a treatment option for COVID-19 because these compounds increase the endosomal pH leading to the inhibition of Cathepsin L. One disadvantage of Cathepsin inhibition is the toxicity. Broad-spectrum inhibition of Cathepsin-L is known to exert toxicity in cells and induce unpredictable side effects. Nevertheless, understanding the mechanism and genetic architecture of the viral response to Cathepsin L might give us some insights in developing an efficient target.

Also read: MIC-Drop: An advancement in large-scale Genome sequencing

References

1. Patel, S., Homaei, A., El-Seedi, H. R., & Akhtar, N. (2018). Cathepsins: Proteases that are vital for survival but can also be fatal. Biomedicine & Pharmacotherapy, 105, 526–532. https://doi.org/10.1016/j.biopha.2018.05.148
2. https://www.news-medical.net/life-sciences/What-are-Cathepsin-Inhibitors.aspx
3. Gomes, C. P., Fernandes, D. E., Casimiro, F., da Mata, G. F., Passos, M. T., Varela, P., Mastroianni-Kirsztajn, G., &Pesquero, J. B. (2020). Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics. Frontiers in Cellular and Infection Microbiology, 10. https://doi.org/10.3389/fcimb.2020.589505

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