CTSS

Official Full Name

cathepsin S

Organism

Homo sapiens

GeneID

1520

Background

The preproprotein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that participates in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules. The mature protein cleaves the invariant chain of MHC class II molecules in endolysosomal compartments and enables the formation of antigen-MHC class II complexes and the proper display of extracellular antigenic peptides by MHC-II. The mature protein also functions as an elastase over a broad pH range. When secreted from cells, this protein can remodel components of the extracellular matrix such as elastin, collagen, and fibronectin. This gene is implicated in the pathology of many inflammatory and autoimmune diseases and, given its elastase activity, plays a significant role in some pulmonary diseases. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2020]

Synonyms

CTSS; cathepsin S; MGC3886; FLJ50259; MGC3886, CTSS;

Bio Chemical Class

Peptidase

Protein Sequence

MKRLVCVLLVCSSAVAQLHKDPTLDHHWHLWKKTYGKQYKEKNEEAVRRLIWEKNLKFVMLHNLEHSMGMHSYDLGMNHLGDMTSEEVMSLMSSLRVPSQWQRNITYKSNPNRILPDSVDWREKGCVTEVKYQGSCGACWAFSAVGALEAQLKLKTGKLVSLSAQNLVDCSTEKYGNKGCNGGFMTTAFQYIIDNKGIDSDASYPYKAMDQKCQYDSKYRAATCSKYTELPYGREDVLKEAVANKGPVSVGVDARHPSFFLYRSGVYYEPSCTQNVNHGVLVVGYGDLNGKEYWLVKNSWGHNFGEEGYIRMARNKGNHCGIASFPSYPEI

Open

Disease

Alopecia, Aneurysm/dissection, Asthma, Autoimmune disease, Bone cancer, Brain cancer, Cardiovascular disease, Chronic obstructive pulmonary disease, Chronic pain, Coeliac disease, Crohn disease, Diabetes mellitus, Digestive system disease, General pain disorder, Hepatic fibrosis/cirrhosis, Lupus erythematosus, Multiple sclerosis, Osteoarthritis, Pain, Postoperative inflammation, Psoriasis, Rheumatoid arthritis, Sjogren syndrome, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

7 +

Discontinued Drug

2 +

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Detailed Information

Cathepsin S (CTSS) is an important member of the cysteine protease C1 family, with its gene located on human chromosome 1q21. Structurally, CTSS is synthesized as a precursor protein (prepro-CTSS) composed of 331 amino acids and consists of three functional domains: a signal peptide region, a propeptide region, and a catalytic active region. The signal peptide, which is 10-20 amino acids long, directs the protein into the endoplasmic reticulum. The propeptide region, containing 98 amino acids, has autoinhibitory functions and assists in proper protein folding. The mature protein region, consisting of 217 amino acids, is responsible for the catalytic function. CTSS displays a typical papain-like fold, comprising three α-helices on the left (L-) and a β-barrel structure on the right (R-). These domains form an active cleft hosting three key catalytic residues: Cys25, His159, and Asn175, which create an acid-base-nucleophile triad. This unique spatial conformation determines CTSS's substrate specificity, with the S2 and S1' binding sites playing crucial roles in substrate recognition and binding.

Expression Regulation Network

CTSS expression is influenced by a precise multilayered regulatory network. At the transcriptional level, various pro-inflammatory factors are involved: IFN-γ activates CTSS transcription via IRF-1 binding to the ISRE element; IL-1β and TNF-α enhance its expression, whereas the anti-inflammatory factor IL-10 inhibits transcription. In the transcription factor network, PU.1 and TFEB act as positive regulators of CTSS transcription, while PPARγ, Blimp-1, and transglutaminase-2 (TG2) inhibit its expression. Several signaling pathways, including the STAT pathway, PI3K/Akt pathway, and Ras/Raf/ERK pathway, also participate in regulation. Post-transcriptionally, RNA-binding proteins play pivotal roles: HuR stabilizes CTSS mRNA through binding to its 3'UTR, more notably under inflammatory or hypoxic conditions, whereas TTP promotes mRNA degradation. Additionally, protein phosphatase 2A (PP2A) can downregulate CTSS expression by enhancing TTP function and inhibiting the MAPK/ERK pathway. Some pathogens, such as Mycobacterium tuberculosis, can also affect CTSS mRNA stability by upregulating miR-106b-5p.

Unique Activity Characteristics and Regulatory Mechanisms

Unlike other cathepsins, CTSS has unique pH-dependent features. While most cathepsins remain active only in acidic environments, CTSS retains catalytic activity in neutral and even mildly alkaline conditions. This enables CTSS to function beyond the lysosomal/endosomal system, notably within the extracellular matrix. CTSS activity is regulated by numerous factors: endogenous inhibitors like cystatin C are crucial negative regulators that competitively bind the active site to inhibit CTSS. Under oxidative stress, the active-site cysteine residue (Cys25) is prone to modification by reactive oxygen species, forming sulfenic acid, reversible by antioxidants. Glycosaminoglycans and other negatively charged polysaccharides can stabilize or modulate CTSS activity by complex formation. Moreover, the reductase GILT ensures CTSS's reduced state to maintain its activity but may also shorten CTSS's half-life, limiting its active duration.

Figure 1 illustrates the regulation of CTSS, showing how inflammatory stimuli affect its expression at transcriptional and post-transcriptional levels, with upregulating mediators in red and downregulating ones in blue. Figure 1. The regulation of CTSS. (Yoo Y, et al., 2022)

Substrate Spectrum and Biological Functions

CTSS possesses a broad substrate spectrum and diverse biological functions. In the immune system, CTSS helps by cutting the invariant chain (Ii) to create CLIP pieces. This process lets outside proteins attach to MHC class II, which helps activate CD4+ T cells. In the reshaping of the extracellular matrix, CTSS can break down different structure proteins like elastin, various types of collagen, and fibronectin. This process can happen outside the cell or inside the cell after the proteins are taken in. CTSS also cleaves non-matrix proteins like cytokines, chemokines, and antibacterial proteins. As a sheddase, CTSS releases external regions of cell adhesion proteins and membrane receptors, such as E-cadherin, affecting epithelial-mesenchymal transition and turnover of cell junctions. CTSS helps control Toll-like receptor 9 signaling by cutting its N- or C-end, which affects how it works.

Pathophysiological Role in Pulmonary Diseases

CTSS is important in the formation and evolution of different lung illnesses. In COPD, CTSS levels are significantly higher in lung tissue, fluid from the airways, and blood. Smoking raises CTSS levels by blocking PP2A, and certain gene variations in CTSS are linked to a higher chance of COPD. Oxidative stress increases the function of CTSS by disrupting its balance with cystatin C. In asthma, CTSS adds to airway inflammation and mucus production by activating protease-activated receptors PAR-2 and PAR-4. CTSS knockouts or drugs that block it can help lower inflammation in the airways and reduce the presence of eosinophils. In cystic fibrosis, CTSS influences the disease by turning on sodium channels in the cells and breaking down protection proteins such as surfactant protein A and LL-37. In idiopathic pulmonary fibrosis, CTSS helps the disease progress by breaking down parts of the supporting structure of the lungs, releasing factors that encourage scarring, and changing how the body responds to inflammation. CTSS works at both normal and acidic pH levels, allowing it to be active at different stages of lung diseases.

Therapeutic Potential and Drug Development

Since CTSS is important in many diseases, focusing on it could lead to effective treatments. Many types of CTSS inhibitors have been created, including small molecules, peptides, and antibodies. These inhibitors mainly reduce CTSS function by attaching to its active site. In early tests, CTSS inhibitors showed good results in treating autoimmune diseases, inflammation, and cancer. Creating specific and safe inhibitors is difficult because CTSS has many different roles in the body. Understanding CTSS's control network and how it works will help create better treatment methods.

Future Research Directions

Future research should further elucidate CTSS's specific mechanisms in different pathological processes, including its interaction networks with other proteases and signaling pathways. Developing novel CTSS inhibitors, particularly those with tissue specificity, will be a key research direction. Additionally, exploring CTSS's potential as a biomarker to establish more accurate disease diagnosis and prognosis assessment systems holds significant importance.

References:

Smyth P, Sasiwachirangkul J, et al. Cathepsin S (CTSS) activity in health and disease - A treasure trove of untapped clinical potential. Mol Aspects Med. 2022 Dec;88:101106.
Yoo Y, Choi E, et al. Therapeutic potential of targeting cathepsin S in pulmonary fibrosis. Biomed Pharmacother. 2022 Jan;145:112245.
A Sousa LH, O Costa C, et al. Complex Regional Pain Syndrome after Carpal Tunnel Syndrome Surgery: A Systematic Review. Neurol India. 2022 Mar-Apr;70(2):491-503.

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