Lysosomal Biogenesis and Degradation Pathways

Lysosomal proenzymes are synthesized in the endoplasmic reticulum (ER) and modified in the cis-Golgi, where they are tagged with mannose-6-phosphate (M6P). In the trans-Golgi, M6P receptors (M6PRs) recognize these tagged proenzymes and sort them into clathrin-coated vesicles (CCVs) for transport to lysosomes. Upon arrival in the lysosome, the acidic environment removes the M6P tag, activating the hydrolases (1). M6PRs also function in retrieving secreted or misrouted lysosomal enzymes, recycling between the Golgi and the plasma membrane (2). Lysosomes degrade cellular components via macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy delivers cargo through autophagosomes that fuse with lysosomes and lysosomes are regenerated from autolysosomal membranes (3). In CMA, HSP70 recognizes KFERQ-tagged proteins, which are unfolded and translocated through LAMP2 without autophagosomes125. Microautophagy involves direct lysosomal uptake via membrane invagination (4). This image was created with BioRender.com.