SCPX(SCP2), <lysosome> Cholesterol = <Golgi apparatus> Cholesterol, Cholesterol lysosome outer leaflet, <vesicle> Sphingolipids = <Golgi apparatus> Sphingolipids, Sphingolipids vesicle, Cholesterol vesicle outer leaflet, Sphingolipids Golgi, <vesicle> Cholesterol = <Golgi apparatus> Cholesterol, Cholesterol vesicle, StARD4, NPC1, Sphingolipids vesicle, LIPA, Cholesterol mitochondrial membrane, MENTHO, 18.104.22.168, Rab-7, <vesicle> Cholesterol = <mitochondrion> Cholesterol, Rab-9, StARD5, Cholesterol vesicle inner leaflet, 22.214.171.124, Sphingolipids vesicle, Cholesteryl ester lysosome, TIP47, <lysosome> Cholesterol = <mitochondrion> Cholesterol, MLN64, Cholesterol endoplasmic reticulum, Cholesteryl ester vesicle, Cholesterol lysosome inner leaflet, Cholesterol Golgi membrane, PBR, NPC2, NPC1, Cholesterol mitochondrial matrix, LIPA, <vesicle> Cholesterol = <endoplasmic reticulum> Cholesterol, NPC2
CF pathway (highlighted in purple on map)
Cultured model CF epithelial cells exhibit intracellular accumulation of unesterified Cholesterol in a manner similar to Niemann-Pick disease. This leads to accumulation of free Cholesterol in late endosomes and lysosomes , , .
Increased Cholesterol and Sphingolipids in punctate endosomal structures indicate a block in the translocation of Cholesterol to the ER and Golgi from late endosomes and lysosomes . Overexpression of RAB9A member RAS oncogene family ( Rab-9 ) clears the punctate Cholesterol accumulations and this might be the consequence of Rab-9 overcoming an endosome-to-Golgi cholesterol trafficking block in CF cells .
Cholesterol and Sphingolipids are transported from early endosomes via the Rab-mediated mechanism. Rab-7 plays a role in the lipid transport from early-to-late endosomes and late endosomes-to-lysosomes. Rab-9 is thought to regulate the late endosome-to- trans -Golgi network (TGN) transport step through its interaction with mannose-6-phosphate receptor binding protein 1 ( TIP47) . Sphingolipids are sorted preferentially to TGN via Rab-7 and Rab-9 interaction . Cholesterol and, especially, Cholesteryl ester can be sorted to both TGN and lysosome. Rab-9 overexpression helps to clear ERC cholesterol accumulation that by itself might be the consequence of Rab-9 overcoming an endosome-to-Golgi Cholesterol trafficking block in F508-expressing cells . In lysosomes, acid cholesterol esterase ( LIPA ) hydrolyses Cholesteryl ester to free Cholesterol and fatty acids . Sphingolipid activator proteins promote Sphingolipids degradation by lysosomal enzymes .
Exchange of Cholestrol content between late endosomes and lysosomes depends upon the ongoing tubulovesicular late endocytic trafficking. It is suspected that Niemann-Pick disease type C1 protein ( NPC1 ) not only mediates Cholesterol efflux from the late endosome membrane inner leaflet to the outer leaflet, but also promotes formation of tubule with Cholesterol from lysosomes and late endosomes toward other intracellular membranes and especially the trans-Golgi network (TGN) , , , .
Niemann-Pick disease type C2 ( NPC2 ) protein and NPC1 promote Cholesterol efflux presumably via a direct interaction with the acceptor membrane. Transfer of Cholesterol to membranes is increased in acidic environment .
StAR-related lipid transfer (START) domain containing proteins 4 and 5 ( StARD4 and StARD5 ) may capture Cholesterol via their MENTAL domain in the late-endosomal membranes. Cholesterol can then be transferred to the cytosolic acceptor protein or to the membrane. START domain containing proteins has been shown to transfer Cholesterol from other donor to acceptor vesicles , , .
Soluble cytosolic proteins like sterol carrier protein 2 ( SCPX(SCP2) ) promote Cholesterol transfer from lysosome membrane to outer mitochondrial membrane . Thus, these proteins promote non-vesicle intracellular Cholesterol transport between intracellular membranes (endosomes, lysosome, endoplasmic reticulum (ER), complex Golgi etc.), cytosolic Chiolesterol/Cholesteryl ester pool, lipid droplets and probably to the inner leaflet of plasma membrane , , , , .