TY - JOUR TI - The relationship between Niemann Pick type C2 protein and lysobisphosphatidic acid in cholesterol transport DO - https://doi.org/doi:10.7282/T3N58PP0 PY - 2016 AB - Niemann Pick Type C (NPC) disease is caused by a mutation in either Niemann Pick C1 or C2 protein, both found in the lysosome and both involved in the export of cholesterol from the lysosome to other parts of the cell. NPC2 has been shown to interact directly with membranes to extract and transport cholesterol while minimizing its exposure to the aqueous environment, but defective NPC2 causes cholesterol accumulation within the lysosome. NPC2 has also been shown to be able to interact with more than one membrane at once. In particular, it appears as though NPC2 has a distinct and specific interaction with the unique lysosomal phospholipid lysobisphosphatidic acid (LBPA), which augments wild type (WT) NPC2 function dramatically. In this study, alanine point mutations in the “hydrophobic knob” region of NPC2, which is proposed to interact with membranes directly, reveal new information about the structure-function relationship of NPC2. Only some of the mutant NPC2 proteins respond to the inclusion of LBPA in membranes, reinforcing that this region is LBPA-sensitive. Past studies have shown that phosphatidylglycerol (PG) is a precursor to LBPA, which is generated along the lysosomal pathway and retains its precursor’s fatty acid composition and glycerol backbone orientation. It has been demonstrated that an increase in lysosomal LBPA content can increase cholesterol efflux from the lysosomes and relieve some of the phenotypical cholesterol accumulation in npc1-/- fibroblasts. We reasoned that because of the interaction between LBPA and NPC2, increasing lysosomal LBPA content in npc2-/- cells would not clear cholesterol from the LE/LY. Thus, WT, npc1-/-, and npc2-/- fibroblasts were supplemented with PG liposomes, which increased cellular LBPA content by at least 2-fold. The increase in LBPA relieved cholesterol accumulation in NPC1 fibroblasts significantly, in agreement with previous literature, but did not diminish cholesterol distribution in NPC2-deficient fibroblasts. This reinforces the critical interaction of NPC2 with LBPA in cholesterol trafficking. In addition, the studies suggest that LBPA supplementation may have therapeutic benefits in patients with mutated NPC1, which account for 95% of NPC cases, but not in patients with defective NPC2. KW - Nutritional Sciences KW - Niemann-Pick diseases KW - Lysosomes LA - eng ER -