| Niemann–Pick type C1 (NPC1) is a large polytopic transmembrane protein that functions as a key cholesterol transporter at the limiting membrane of late endosomes and lysosomes, where it coordinates the egress of unesterified cholesterol from the lysosomal lumen to the endoplasmic reticulum, Golgi, and plasma membrane. NPC1 is predicted to span the membrane multiple times with a sterol‑sensing domain and a large N‑terminal lumen‑facing loop that binds cholesterol delivered by the soluble lysosomal protein NPC2, while its C‑terminal cytoplasmic tail contains motifs that regulate endosomal targeting and trafficking, enabling NPC1 to act as a membrane‑embedded node that couples luminal cholesterol capture to downstream vesicular and nonvesicular cholesterol transport. NPC2 binds lumenal free cholesterol and transfers it to the N‑terminal domain of NPC1, after which NPC1 engages the sterol‑sensing domain and facilitates cholesterol export to organelles such as the ER via oxysterol‑binding protein‑related protein 5 (ORP5) and other lipid‑transfer factors, thereby maintaining intracellular lipid homeostasis and preventing toxic accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. Loss‑of‑function mutations in NPC1 cause Niemann–Pick type C disease, a lysosomal storage disorder characterized by progressive neurodegeneration, hepatosplenomegaly, lung dysfunction, and neuroinflammation, and even partial dysregulation of NPC1‑mediated trafficking is implicated in atherosclerosis, viral entry (notably filoviruses such as Ebola that exploit NPC1 for endosomal membrane fusion), and altered immune and neuronal signaling. |
Lane 1: U87MG, Lane 2: C6, Lane 3: H-4-II-E, Lane 4: 3T3-L1
