Abstract
We have developed a suitable heterologous cell expression system to study the localization, trafficking, and site(s) of function of the human ABCG1 transporter. Increased plasma membrane (PM) and late endosomal (LE) cholesterol generated by ABCG1 was removed by lipoproteins and liposomes, but not apoA-I. Delivery of ABCG1 to the PM and LE was required for ABCG1-mediated cellular cholesterol efflux. ABCG1 LEs frequently contacted the PM, providing a collisional mechanism for transfer of ABCG1-mobilized cholesterol, similar to ABCG1-mediated PM cholesterol efflux to lipoproteins. ABCG1-mobilized LE cholesterol also trafficked to the PM by a non-vesicular pathway. Transfer of ABCG1-mobilized cholesterol from the cytoplasmic face of LEs to the PM and concomitant removal of cholesterol from the outer leaflet of the PM bilayer by extracellular acceptors suggests that ABCG1 mobilizes cholesterol on both sides of the lipid bilayer for removal by acceptors. ABCG1 increased uptake of HDL into LEs, consistent with a potential ABCG1-mediated cholesterol efflux pathway involving HDL resecretion. Thus, ABCG1 at the PM mobilizes PM cholesterol and ABCG1 in LE/LYS generates mobile pools of cholesterol that can traffic by both vesicular and non-vesicular pathways to the PM where it can also be transferred to extracellular acceptors with a lipid surface.
Highlights
Cholesterol plays critical roles in maintaining proper membrane structure and function through its interactions with other membrane lipids and proteins
We subsequently reported that ABCG1 resides on the cell surface as well as in late endosomes that shuttle back to the cell surface, and that ABCG1 mobilizes a pool of cholesterol on the cell surface that is distinctive from pools mobilized by ABCA1 [11]
Our studies reveal that ABCG1-mediated enhancement of cellular cholesterol efflux requires delivery of ABCG1 from its site of synthesis in the ER, to the plasma membrane and late endocytic compartments, and that ABCG1 rapidly cycles between endosomes and the cell surface
Summary
Cholesterol plays critical roles in maintaining proper membrane structure and function through its interactions with other membrane lipids and proteins. A growing number of membrane proteins that reside at the plasma membrane, in late endocytic compartments, or both, have been found to play critical roles in intracellular cholesterol trafficking, including ABCA1 [1,2], ABCA3 [3,4], NPC1 [5], MLN64 [4], among others. Our studies reveal that ABCG1-mediated enhancement of cellular cholesterol efflux requires delivery of ABCG1 from its site of synthesis in the ER, to the plasma membrane and late endocytic compartments, and that ABCG1 rapidly cycles between endosomes and the cell surface.
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