The delivery of endocytosed cargo to lysosomes

Abstract

In mammalian cells, endocytosed cargo that is internalized through clathrin-coated pits/vesicles passes through early endosomes and then to late endosomes, before delivery to lysosomes for degradation by proteases. Late endosomes are MVBs (multivesicular bodies) with ubiquitinated membrane proteins destined for lysosomal degradation being sorted into their luminal vesicles by the ESCRT (endosomal sorting complex required for transport) machinery. Cargo is delivered from late endosomes to lysosomes by kissing and direct fusion. These processes have been studied in live cell experiments and a cell-free system. Late endosome-lysosome fusion is preceded by tethering that probably requires mammalian orthologues of the yeast HOPS (homotypic fusion and vacuole protein sorting) complex. Heterotypic late endosome-lysosome membrane fusion is mediated by a trans-SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) complex comprising Syntaxin7, Vti1b, Syntaxin8 and VAMP7 (vesicle-associated membrane protein 7). This differs from the trans-SNARE complex required for homotypic late endosome fusion in which VAMP8 replaces VAMP7. VAMP7 is also required for lysosome fusion with the plasma membrane and its retrieval from the plasma membrane to lysosomes is mediated by its folded N-terminal longin domain. Co-ordinated interaction of the ESCRT, HOPS and SNARE complexes is required for cargo delivery to lysosomes.

Mutations associated with Charcot–Marie–Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome–autophagy pathways

“…S3B). Together, these results suggest that SIMPLE WT protein, similarly to many integral membrane proteins, mainly relies on the endosome-tolysosome sorting pathway for its degradation (Babst, 2004;Luzio et al, 2009). By contrast, we found that the protein levels of SIMPLE W116G and P135T mutants were significantly increased upon proteasome inhibition by MG132, autophagy inhibition by 3-MA or lysosome inhibition by CQ or NH 4 Cl (Fig.…”

The cellular uptake mechanism, intracellular transportation, and exocytosis of polyamidoamine dendrimers in multidrug-resistant breast cancer cells

“…In the CME pathway, the PAMAM-NH 2 internalized from the plasma membrane is integrated into late endosomes and then delivered to lysosomes. [38][39][40] Although PAMAM-NH 2 has a proton sponge effect, the more complicated internal environment of lysosomes in resistant cells results in more difficult lysosomes escape in MCF-7/ADR cells.…”

Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology

“…Cargo destined for degradation is trafficked through endocytic, phagocytic or autophagic routes, after which these compartments mature and undergo fusion with lysosomes. [1][2][3][4] The degradative capacity of lysosomes is crucial for physiological processes such as nutrient provision, termination of signaling pathways, microbial killing and autophagic clearance of protein aggregates. As such, impairment of lysosomal function can manifest in diseased states including cancer, lysosomal storage disorders, and neurodegenerative diseases.…”