Abstract
The cellular membrane of eukaryotes consists of phospholipids, sphingolipids, cholesterol and membrane proteins. Among them, cholesterol is crucial for various cellular events (e.g., signaling, viral/bacterial infection, and membrane trafficking) in addition to its essential role as an ingredient of steroid hormones, vitamin D, and bile acids. From a micro-perspective, at the plasma membrane, recent emerging evidence strongly suggests the existence of lipid nanodomains formed with cholesterol and phospholipids (e.g., sphingomyelin, phosphatidylserine). Thus, it is important to elucidate how cholesterol behaves in membranes and how the behavior of cholesterol is regulated at the molecular level. To elucidate the complexed characteristics of cholesterol in cellular membranes, a couple of useful biosensors that enable us to visualize cholesterol in cellular membranes have been recently developed by utilizing domain 4 (D4) of Perfringolysin O (PFO, theta toxin), a cholesterol-binding toxin. This review highlights the current progress on development of novel cholesterol biosensors that uncover new insights of cholesterol in cellular membranes.
Highlights
Cells produce cholesterol through the de novo pathway in the endoplasmic reticulum (ER) and this lipid is transported to cellular compartments via either vesicular or non-vesicular routes [1]
A part of cholesterol is esterified with fatty acids by acyl-CoA cholesterol acyl transferase (ACAT) in ER and the esterified cholesterol is stored in lipid droplets (LDs) [1]
Cholesterol derived from low-density lipoprotein (LDL) utilizes two late endosomal proteins, NPC1 and NPC2, to escape from lumen of the late endosomes (LEs) and cholesterol is delivered to other cellular membranes [1,2,3]
Summary
Cells produce cholesterol through the de novo pathway in the endoplasmic reticulum (ER) and this lipid is transported to cellular compartments via either vesicular or non-vesicular routes [1]. Small hydroxyl with phospholipids containing large polar (flip-flop) head groups longthe saturated fattygroup acyl of chains like cholesterol is insufficient to shield the comparatively large hydrophobic group of cholesterol from sphingomyelin [1,14,15,16] This concept has generated a notion that cholesterol and sphingolipids water molecules in the lipid bilayer. Fluorophore-labeled cholesterols cannot distinguish cholesterol in the cytosolic leaflets and luminal these probes can beleaflets used for live-cell imaging, addition ofPerfringolysin fluorophores to cholesterol (exofacial) of cellular membranes ([38]; Figure 2). One possesses four domains and, among them, domain 4 (D4) recognizes the hydroxyl group at the big issue is that filipin and fluorophore-labeled cholesterols cannot distinguish cholesterol in the cytosolic leaflets and luminal (exofacial) leaflets of cellular membranes ([38]; Figure 2).
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