Figure 3.

Organellar contact site and fusion with lysosome. (A). Lysosome-ER: Lysosome-ER contact site regulates ER Ca²⁺ release. (1) Lysosome-ER contact site shuttles free cholesterol from the lysosome to ER via concerted action of lysosomal membrane-localized protein, NPC1 and ER membrane proteins, VAPA (vesicle-associated membrane protein (VAMP)-associated ER protein A) and VAPB and a lipid-transfer protein, ORP1L (oxysterol-binding protein-related protein 1L). (2) Low cellular cholesterol level activates ORP1L, which then triggers the formation of a contact site between ER and lysosomal membrane. ER-resident protein VAP anchors with lysosomal Rab7-RILP (Rab7-interacting protein) to initiate the movement of lysosomes to plus-end or towards the cell periphery. (3) NAADP (nicotinic acid adenine dinucleotide phosphate), a Ca²⁺ mobilizing entity and IP3 receptor agonist mobilizes lysosomal Ca²⁺ and facilitates ER Ca²⁺ release into the cytosol. (B). Lysosome-Mitochondria: Lysosome-mitochondria contract site mediates the bidirectional regulation of lysosome and mitochondria dynamics. (1) Mitochondria forms a contact with the lysosome via lysosomal bound Rab7-GTP. This contact site is disrupted by mitochondrial fission 1 membrane protein, FIS1 and recruits TBC1D15 (TBC1 Domain Family Member 15) which hydrolyzes Rab7-GTP to Rab7-GAP. (2) Lysosomal mucolipin channel, TRPML1 (Transient Receptor Potential Cation Channel, Mucolipin subfamily) governs mitochondria homeostasis by sensing and scavenging mitochondrial ROS (reactive oxygen species). TRPML1 is activated by ROS that induces Ca²⁺ release from the lysosomal lumen and activates nuclear TFEB translocation in a calcineurin-dependent manner. TFEB induces lysosome biogenesis and autophagy to clear damaged mitochondria and scavenge ROS. (C). Lysosome-Late endosome: The fusion of lysosome and late endosome occurs via tethering processes, which involves; (1) coupling of small GTPase Rab7, Rab7-interacting protein (RIPL) and vacuole protein sorting (HOPS) complex, (2) interaction of Rab7, VPS18 and VPS39 (3) Rab7, Arf-like (Ar18b) and Rab7 effector PLEKHM1 (pleckstrin homology domain-containing protein family member 1 and (4) formation of Trans-SNARE assembly composed of syntaxin-7 (STX7, Qa-SNARE), VTI1B (VPS10 tail interactor-1B, Qb-SNARE) and syntaxin-8 (STX8, Qc-SNARE). (D). Lysosome-autophagosome: The fusion of lysosome and autophagosome occurs via (1) HOPS complex and Rab7 effector protein, PLEKHM1 which binds to HOP via LC3-interacting region (LIR) (2) BLOC-1 related complex (BORC1) that recruits Rab7 and HOPS for tethering and (3) enabling trans-SNARE complex formation of STX17-VAMP8-SNAP29 to induce autophagosome-lysosome fusion.