Figure 2.

Sorting pathways to the endolysosomes. Newly synthesized lysosomal proteins are transported to the Golgi apparatus from where they reach the endosomes and, subsequently the lysosomes. One of the main transport pathways followed by these proteins is a direct route from the TGN to the endosomes (1). The lysosomal transmembrane proteins and acid hydrolase receptors (MPRs, sortilin, SEZ6L2) that are bound to their ligands are packaged at the TGN in clathrin-coated carriers that travel toward the endosomes. This packaging is driven by the binding of typical cytosolic tyrosine- or dileucine-based sorting signals, or of atypical motifs, to clathrin adaptor proteins (directly or through some other proteins). Alternatively, some transmembrane proteins (including LAMP1 and LAMP2) can be transported directly from the TGN to the endosomes in non-clathrin-coated vesicles (“LAMP carriers”) that are positive for hVps41 and VAMP7 (2). Lysosomal proteins that are not packaged in transport vesicles at the TGN, and escape to the cell surface as a consequence, can be recaptured by clathrin-mediated internalization, which is also based on the recognition of cytosolic sorting motifs by PM clathrin adaptor proteins (3). In addition, LAMP3 has been found to enter the endolysosomal system by caveolin-mediated internalization (4). Of note, some lysosomal proteins may piggyback on others to enter some of these pathways (as indicated in Table 1). The cells can also acquire some lysosomal proteins from other cells, e.g., through the capture of microvesicles by clathrin-dependent and -independent mechanisms (5) or subsequently to the transfer of exogenous lysosomes through nanotube-like structures tunneling between some cells (6). Lastly, some proportion of lysosomal proteins could, hypothetically, bypass the Golgi apparatus to reach endolysosomes or autophagosomes (which could then fuse with lysosomes) directly from the ER, or after sorting from the ER to the PM and subsequent internalization from this site (7).