9.C.26.  The Lysosome-Plasma Membrane-Fusion/Exocytosis (LPMFE) Family 

The existence of "unconventional" secretory routes, which play a crucial role in exporting cytosolic proteins outside the cell in response to intrinsic demands, external cues, and environmental changes has been documented (see for example, TC# 9.A.48 and 9.C.17). Lysosomes are dynamic organelles positioned at the crossroads of multiple intracellular trafficking pathways, endowed with the capacity to fuse with the plasma membrane. They are recognized for their key role in unconventional protein secretion. The recent recognition of lysosomal transport and exocytosis in the unconventional secretion of cargo proteins provides insight into an understanding of numerous physiological processes.

Lysosomes are at the crossroad of several intracellular trafficking pathways. Newly synthesized lysosomal hydrolases and lysosomal membrane proteins (LMPs) contain an N-terminal hydrophobic signal sequence or transmembrane domains that allow their targeting and insertion into the ER. Once transported through the Golgi apparatus, lysosomal proteins are then subjected to post-translational modifications including the addition of mannose-6-phosphate (M6P) residues (Néel et al. 2024). M6P residues are essential for protein sorting at the TGN, where lysosomal proteins are packaged into clathrin-coated intermediates and diverted from the biosynthetic secretory pathway to the endocytic pathway for delivery to lysosomes. Post-Golgi clathrin-coated carriers are mainly targeted directly to the endolysosomal pathway (Polishchuk et al. 2006). This pathway relies on coordinated membrane fluxes involving organelle maturation and membrane fission/fusion events (Huotari and Helenius 2011). In addition to the well-characterized direct transport to lysosomes, several newly synthesized LMPs follow an indirect pathway. This pathway entails the transport of LMPs to the PM, their subsequent internalization into early endosomes, and delivery to LEs and lysosomes (Braun et al. 1989). The spatiotemporal dynamics of these distinct pathways have been suggested. In addition to functional factors and extracellular substrates transported to lysosomes via the secretory and endocytic pathways, cytoplasmic material is targeted to lysosomes through sequestration by macroautophagy. In the autophagic process, cytoplasmic substrates are initially sequestered within a cup-shaped double membrane structure known as the phagophore (see TC Family 9.A.15), which upon expansion and complete closure forms the autophagosome. Autophagosomes are then transported along the microtubules and ultimately fuse with lysosomes (Bento et al. 2016; Bento et al. 2016). Along the endocytic and autophagic pathways, the fusion of lysosomes with LE/MVBs and autophagosomes forms endolysosomes and autolysosomes, respectively. From these hybrid compartments, lysosomes or terminal/storage lysosomes are reformed via lysosomal regeneration cycles, through processes of tubulation, maturation, and content condensation. The terms “lysosomes,” “endolysosomes,” or “LE/lysosomes” are used alternatively due to uncertainty regarding the exact nature of the described organelles. 

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