As mentioned previously, the intracellular trafficking leading to the delivery of many soluble lysosomal enzymes to late endosomes and lysosomes involves the M-6-P signal and its receptor. All membrane proteins destined for lysosomes (and late endosomes) are synthesized in the rER and transported to and sorted in the Golgi apparatus. However, they do not contain the M-6-P signals and must be targeted to lysosomes by a different mechanism. The targeting signal for integral membrane proteins is represented by a short cytoplasmic C-terminus domain, which is recognized by adaptin protein complexes and packaged into clathrin-coated vesicles. These proteins reach their destination by one of two pathways:  In the constitutive secretory pathway, limps exit the
Golgi apparatus in coated vesicles and are delivered to the cell surface. From here, they are endocytosed and, via the early and late endosomal compartments, finally reach lysosomes (Fig. 2.20).
 In the Golgi-derived coated vesicle secretory pathway, limps, after sorting and packaging, exit the Golgi  apparatus in clathrin-coated vesicles (see Fig. 2.20). These transport vesicles travel and fuse with late endosomes as a  result of interaction between endosome-specific components of v-SNARE and t-SNARE docking proteins (see page 34).
Three different pathways deliver material for intracellular digestion in lysosomes.
Depending on the nature of the digested material, different pathways deliver material for digestion within the lysosomes (Fig. 2.21). In the digestion process, most of the digested material comes from endocytotic processes; however, the cell also uses lysosomes to digest its own obsolete parts, nonfunctional organelles, and unnecessary molecules. Three pathways for digestion exist:  Extracellular large particles such as bacteria, cell debris, and other foreign materials are engulfed in the process of phagocytosis. A phagosome, formed as the material is internalized within the cytoplasm, subsequently receives hydrolytic enzymes to become a late endosome, which matures into a lysosome.
 Extracellular small particles such as extracellular proteins, plasma-membrane proteins, and ligand–receptor complexes are internalized by pinocytosis and receptor-mediated endocytosis. These particles follow the endocytotic pathway through early and late endosomal compartments and are finally degraded in lysosomes.
 Intracellular particles such as entire organelles, cytoplasmic proteins, and other cellular components are isolated from the cytoplasmic matrix by endoplasmic reticulum membranes, transported to lysosomes, and degraded. This process is called autophagy (see page 41).
FIGURE 2.20 • Lysosome biogenesis. This diagram shows regulated and constitutive pathways for delivery of lysosomal specifc membrane proteins into early and late endosomes. The lysosomal membrane possesses highly glycosylated specifc membrane proteins that protect the membrane from digestion by lysosomal enzymes. These lysosome-specifc proteins are synthesized in the rough endoplasmic reticulum, transported to the Golgi apparatus, and reach their destination by two pathways. Blue arrows indicate the constitutive secretory pathway in which certain lysosomal membrane proteins exit the Golgi apparatus and are delivered to the cell surface. From there they are endocytosed and, via the early and late endosomal compartments, fnally reach lysosomes. Green arrows indicate the endosomal Golgiderived coated vesicle secretory pathway. Here, other lysosomal proteins, after sorting and packaging, exit the Golgi apparatus in clathrin-coated vesicles to fuse with early and late endosomes.