Describe the step involved in the trafficking of soluble lysosomal enzymes from the trans-Golgi network and cell surface to lysosomes

The trafficking of soluble lysosomal enzymes from the trans-Golgi network (TGN) and sometimes the cell surface to the lysosomes is a highly regulated, multistep process. This mechanism ensures that lysosomal hydrolases are specifically recognized, sorted and delivered to their correct destination without getting misdirected or secreted. This sorting is based mainly on mannose-6-phosphate (M6P) tags present on the enzymes, which act as a signal for targeting.

There are five major steps in this trafficking pathway:

1. Tagging with Mannose-6-Phosphate in the Golgi Apparatus

Soluble lysosomal enzymes are first synthesized in the rough endoplasmic reticulum (RER) and transported to the cis-Golgi. Inside the Golgi, they are modified by a two-step enzymatic reaction:
  • An enzyme called N-acetylglucosamine-1-phosphotransferase attaches a phosphorylated N-acetylglucosamine (GlcNAc-P) group to the mannose residue of the N-linked oligosaccharides on the enzyme.
  • Another enzyme removes the GlcNAc group, exposing the mannose-6-phosphate (M6P) residue, which acts as a lysosomal targeting signal.

2. Recognition by Mannose-6-Phosphate Receptors (MPRs) in the Trans-Golgi Network

In the trans-Golgi network, the M6P-tagged enzymes are recognized and bound by mannose-6-phosphate receptors (MPRs). These receptors are transmembrane proteins that selectively bind to M6P-tagged cargo in the slightly acidic pH of the Golgi.

3. Packaging into Clathrin-Coated Vesicles

The MPRs carrying the M6P-tagged enzymes are recruited into clathrin-coated vesicles with the help of adaptor proteins (like AP1). Clathrin provides the mechanical force needed to form the vesicle, which then buds off from the TGN.

4. Delivery to Endosomes and Dissociation

The vesicles fuse with early endosomes, where the internal environment is more acidic than the trans-Golgi network (TGN). This drop in pH causes the enzymes to dissociate from the MPRs. The free enzymes are then transported further to the late endosome and eventually to the lysosome, where they become active.

5. Recycling of Mannose-6-Phosphate Receptors

After delivering their cargo, the MPRs are recycled back to the trans-Golgi or sometimes to the plasma membrane through retromer-coated vesicles. At the plasma membrane, MPRs can also capture any escaped enzymes from the extracellular environment and return them to lysosomes through endocytosis, forming an alternative pathway from the cell surface to lysosomes.
The trafficking of soluble lysosomal enzymes from the trans-Golgi network (TGN) and sometimes the cell surface to the lysosomes is a highly regulated, multistep process. This mechanism ensures that lysosomal hydrolases are specifically recognized, sorted and delivered to their correct destination without getting misdirected or secreted. This sorting is based mainly on mannose-6-phosphate (M6P) tags present on the enzymes, which act as a signal for targeting. There are five major steps in this trafficking pathway:








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