Cathepsins contain a signal peptide (blue) that directs insertion of the nascent polypeptide chain into the ER. Within the ER, the signal peptide is cleaved and the protein folds with the assistance of the proregion (red). Disulfide bond formation (indicated by S-S) and N-linked glycosylation with high-mannose glycans subsequently occurs in the ER. Within the Golgi, mannose residues are phosphorylated to form m6p, which is used to route the protein into the endosomal/lysosomal compartment via the m6p receptor. Upon initial acidification of the endosome, cathepsins are activated, which leads to cleavage of the proregion and further activation of the cathepsin, resulting in further proteolytic processing in the lysosome into heavy and light chains (yellow). A portion of the cathepsins is not converted to the m6p form and as a result is shunted into the exocytosis pathway. Conversion to m6p appears to be rate limiting, as overexpression of a given cathepsin greatly increases the proportion of the enzyme in this pathway. Ribbon diagrams depict the structure of mature cathepsin L in the extracellular matrix and in the lysosome. The ribbon colors correspond to the colors used in the diagram on the left.