CTSL

Function

Thiol protease important for the overall degradation of proteins in lysosomes (Probable). Plays a critical for normal cellular functions such as general protein turnover, antigen processing and bone remodeling. Involved in the solubilization of cross-linked TG/thyroglobulin and in the subsequent release of thyroid hormone thyroxine (T4) by limited proteolysis of TG/thyroglobulin in the thyroid follicle lumen (By similarity). In neuroendocrine chromaffin cells secretory vesicles, catalyzes the prohormone proenkephalin processing to the active enkephalin peptide neurotransmitter (By similarity). In thymus, regulates CD4(+) T cell positive selection by generating the major histocompatibility complex class II (MHCII) bound peptide ligands presented by cortical thymic epithelial cells. Also mediates invariant chain processing in cortical thymic epithelial cells (By similarity). Major elastin-degrading enzyme at neutral pH. Accumulates as a mature and active enzyme in the extracellular space of antigen presenting cells (APCs) to regulate degradation of the extracellular matrix in the course of inflammation (By similarity). Secreted form generates endostatin from COL18A1 (PubMed:10716919). Critical for cardiac morphology and function. Plays an important role in hair follicle morphogenesis and cycling, as well as epidermal differentiation (By similarity). Required for maximal stimulation of steroidogenesis by TIMP1 (By similarity).

(Microbial infection) In cells lacking TMPRSS2 expression, facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via a slow acid-activated route with the proteolysis of coronavirus spike (S) glycoproteins in lysosome for entry into host cell (PubMed:16339146, PubMed:18562523, PubMed:32142651, PubMed:32221306, PubMed:37990007). Proteolysis within lysosomes is sufficient to activate membrane fusion by coronaviruses SARS-CoV and EMC (HCoV-EMC) S as well as Zaire ebolavirus glycoproteins (PubMed:16081529, PubMed:18562523, PubMed:26953343).

Isoform 2

Functions in the regulation of cell cycle progression through proteolytic processing of the CUX1 transcription factor (PubMed:15099520). Translation initiation at downstream start sites allows the synthesis of isoforms that are devoid of a signal peptide and localize to the nucleus where they cleave the CUX1 transcription factor and modify its DNA binding properties (PubMed:15099520).

Post-translational modifications

During export along the endocytic pathway, pro-CTSL undergoes several proteolytic cleavages to generate the CTSL single-chain and two-chain mature forms, composed of a heavy chain linked to a light chain by disulfide bonds (By similarity). Autocleavage; produces the single-chain CTSL after cleavage of the propeptide. The cleavage can be intermolecular (PubMed:9468501).

Sequence Similarities

Belongs to the peptidase C1 family.

Cellular localization

• Lysosome
• Apical cell membrane
• Peripheral membrane protein
• Extracellular side
• Cytoplasmic vesicle
• Secretory vesicle
• Chromaffin granule
• Secreted
• Extracellular space
• Secreted
• Localizes to the apical membrane of thyroid epithelial cells. Released at extracellular space by activated dendritic cells and macrophages.
• Isoform 2
• Nucleus
• Translation initiation at downstream start sites allows the synthesis of isoforms that are devoid of a signal peptide and do not transit through the endoplasmic reticulum to localize to the nucleus (PubMed:15099520). Nuclear location varies during the cell cycle, with higher levels during S phase (PubMed:15099520).

Alternative names

CTSL1, CTSL, Procathepsin L, Cathepsin L1, Major excreted protein, MEP

Database links

swissprot:P07711 omim:116880 swissprot:P09668 swissprot:P43235 entrezGene:1514