UniProt functional annotation for P07711



	UniProt functional annotation for P07711

UniProt code: P07711.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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). {ECO:0000250|UniProtKB:P06797, ECO:0000250|UniProtKB:P07154, ECO:0000250|UniProtKB:P25975, ECO:0000269|PubMed:10716919, ECO:0000305}.

Function: [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). {ECO:0000269|PubMed:15099520}.

Function: (Microbial infection) Facilitates human coronaviruses SARS- CoV and SARS-CoV-2 infections via proteolysis of coronavirus spike (S) glycoproteins in lysosome for entry into host cell (PubMed:32142651, PubMed:32221306, PubMed:16339146, PubMed:18562523). 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:26953343, PubMed:18562523). {ECO:0000269|PubMed:16081529, ECO:0000269|PubMed:16339146, ECO:0000269|PubMed:18562523, ECO:0000269|PubMed:26953343, ECO:0000269|PubMed:32142651, ECO:0000269|PubMed:32221306, ECO:0000269|PubMed:32855215}.

Catalytic activity: Reaction=Specificity close to that of papain. As compared to cathepsin B, cathepsin L exhibits higher activity toward protein substrates, but has little activity on Z-Arg-Arg-NHMec, and no peptidyl- dipeptidase activity.; EC=3.4.22.15; Evidence={ECO:0000269|PubMed:9468501};

Activity regulation: Inhibited by the propeptide produced by autocleavage (PubMed:9468501). Long isoform of CD74/Ii chain stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of APCs. IFNG enhances the conversion into the CTSL mature and active form (By similarity). Inhibited by CST6. Inhibited by the glycopeptide antibiotic teicoplanin (PubMed:26953343). Inhibited by amantadine (PubMed:32361028). {ECO:0000250|UniProtKB:P06797, ECO:0000269|PubMed:26953343, ECO:0000269|PubMed:30425301, ECO:0000269|PubMed:32361028, ECO:0000269|PubMed:9468501}.

Biophysicochemical properties: pH dependence: Optimum pH is 5.5, also active at pH 7.0 with CUX1 as substrate. {ECO:0000269|PubMed:10716919, ECO:0000269|PubMed:15099520, ECO:0000269|PubMed:18562523, ECO:0000269|PubMed:9468501};

Subunit: Dimer of a heavy and a light chain linked by disulfide bonds. Interacts with Long isoform of CD74/Ii chain; the interaction stabilizes the conformation of mature CTSL. {ECO:0000250|UniProtKB:P06797}.

Subcellular location: Lysosome {ECO:0000250|UniProtKB:P06797}. Apical cell membrane {ECO:0000250|UniProtKB:P06797}; Peripheral membrane protein {ECO:0000250|UniProtKB:P06797}; Extracellular side {ECO:0000250|UniProtKB:P06797}. Cytoplasmic vesicle, secretory vesicle, chromaffin granule {ECO:0000250|UniProtKB:P25975}. Secreted, extracellular space {ECO:0000250|UniProtKB:P06797}. Secreted {ECO:0000250|UniProtKB:P06797}. Note=Localizes to the apical membrane of thyroid epithelial cells. Released at extracellular space by activated dendritic cells and macrophages. {ECO:0000250|UniProtKB:P06797}.

Subcellular location: [Isoform 2]: Nucleus {ECO:0000269|PubMed:15099520}. Note=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, whith higher levels during S phase (PubMed:15099520). {ECO:0000269|PubMed:15099520}.

Ptm: 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). {ECO:0000250|UniProtKB:P06797, ECO:0000269|PubMed:9468501}.

Similarity: Belongs to the peptidase C1 family. {ECO:0000255|PROSITE- ProRule:PRU10088, ECO:0000255|PROSITE-ProRule:PRU10089, ECO:0000255|PROSITE-ProRule:PRU10090}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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). {ECO:0000250\|UniProtKB:P06797, ECO:0000250\|UniProtKB:P07154, ECO:0000250\|UniProtKB:P25975, ECO:0000269\|PubMed:10716919, ECO:0000305}.



Function:		[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). {ECO:0000269\|PubMed:15099520}.



Function:		(Microbial infection) Facilitates human coronaviruses SARS- CoV and SARS-CoV-2 infections via proteolysis of coronavirus spike (S) glycoproteins in lysosome for entry into host cell (PubMed:32142651, PubMed:32221306, PubMed:16339146, PubMed:18562523). 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:26953343, PubMed:18562523). {ECO:0000269\|PubMed:16081529, ECO:0000269\|PubMed:16339146, ECO:0000269\|PubMed:18562523, ECO:0000269\|PubMed:26953343, ECO:0000269\|PubMed:32142651, ECO:0000269\|PubMed:32221306, ECO:0000269\|PubMed:32855215}.


Catalytic activity:		Reaction=Specificity close to that of papain. As compared to cathepsin B, cathepsin L exhibits higher activity toward protein substrates, but has little activity on Z-Arg-Arg-NHMec, and no peptidyl- dipeptidase activity.; EC=3.4.22.15; Evidence={ECO:0000269\|PubMed:9468501};
Activity regulation:		Inhibited by the propeptide produced by autocleavage (PubMed:9468501). Long isoform of CD74/Ii chain stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of APCs. IFNG enhances the conversion into the CTSL mature and active form (By similarity). Inhibited by CST6. Inhibited by the glycopeptide antibiotic teicoplanin (PubMed:26953343). Inhibited by amantadine (PubMed:32361028). {ECO:0000250\|UniProtKB:P06797, ECO:0000269\|PubMed:26953343, ECO:0000269\|PubMed:30425301, ECO:0000269\|PubMed:32361028, ECO:0000269\|PubMed:9468501}.
Biophysicochemical properties:		pH dependence: Optimum pH is 5.5, also active at pH 7.0 with CUX1 as substrate. {ECO:0000269\|PubMed:10716919, ECO:0000269\|PubMed:15099520, ECO:0000269\|PubMed:18562523, ECO:0000269\|PubMed:9468501};
Subunit:		Dimer of a heavy and a light chain linked by disulfide bonds. Interacts with Long isoform of CD74/Ii chain; the interaction stabilizes the conformation of mature CTSL. {ECO:0000250\|UniProtKB:P06797}.
Subcellular location:		Lysosome {ECO:0000250\|UniProtKB:P06797}. Apical cell membrane {ECO:0000250\|UniProtKB:P06797}; Peripheral membrane protein {ECO:0000250\|UniProtKB:P06797}; Extracellular side {ECO:0000250\|UniProtKB:P06797}. Cytoplasmic vesicle, secretory vesicle, chromaffin granule {ECO:0000250\|UniProtKB:P25975}. Secreted, extracellular space {ECO:0000250\|UniProtKB:P06797}. Secreted {ECO:0000250\|UniProtKB:P06797}. Note=Localizes to the apical membrane of thyroid epithelial cells. Released at extracellular space by activated dendritic cells and macrophages. {ECO:0000250\|UniProtKB:P06797}.
Subcellular location:		[Isoform 2]: Nucleus {ECO:0000269\|PubMed:15099520}. Note=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, whith higher levels during S phase (PubMed:15099520). {ECO:0000269\|PubMed:15099520}.
Ptm:		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). {ECO:0000250\|UniProtKB:P06797, ECO:0000269\|PubMed:9468501}.
Similarity:		Belongs to the peptidase C1 family. {ECO:0000255\|PROSITE- ProRule:PRU10088, ECO:0000255\|PROSITE-ProRule:PRU10089, ECO:0000255\|PROSITE-ProRule:PRU10090}.