Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export

Abstract

The intracellular transport of cholesterol is subject to tight regulation. The structure of the lysosomal integral membrane protein type 2 (LIMP-2, also known as SCARB2) reveals a large cavity that traverses the molecule and resembles the cavity in SR-B1 that mediates lipid transfer. The detection of cholesterol within the LIMP-2 structure and the formation of cholesterol − like inclusions in LIMP-2 knockout mice suggested the possibility that LIMP2 transports cholesterol in lysosomes. We present results of molecular modeling, crosslinking studies, microscale thermophoresis and cell-based assays that support a role of LIMP-2 in cholesterol transport. We show that the cavity in the luminal domain of LIMP-2 can bind and deliver exogenous cholesterol to the lysosomal membrane and later to lipid droplets. Depletion of LIMP-2 alters SREBP-2-mediated cholesterol regulation, as well as LDL-receptor levels. Our data indicate that LIMP-2 operates in parallel with Niemann Pick (NPC)-proteins, mediating a slower mode of lysosomal cholesterol export.

Lysosome biology in autophagy

“…These mechanisms are still mostly unclear, especially with respect to lipid egress. NPC1, NPC2 54 and LIMP2 55 have been identified to transport cholesterol from the lysosomal lumen to the lysosomal membrane but little is known about the transport of other lipid products. As indicated by recent studies, lipids may be transferred from lysosomal membranes to other organellar membranes via membrane contact sites 56 .…”

Phagocytosis by the Retinal Pigment Epithelium: Recognition, Resolution, Recycling

“…This requires a system of cholesterol-binding proteins that support movement of the hydrophobic molecule through tunnel-like structures. It can be achieved by the concerted action of Niemann-Pick type C (NPC) 1 and 2 (142) as well as by LIMP-2 (143). Niemann-Pick proteins are indeed necessary for normal retinal function (144).…”

Modeling Lysosomal Storage Diseases in the Zebrafish

“…Five zebrafish models have been characterized for AMRF and cystinosis. AMRF is caused by mutations in SCARB2, which encodes LIMP-2, a lysosomal integral membrane protein with various functions including receptor recognition of phospholipids and viruses, cholesterol transport, and the transport of β-GBA (mutated in Gaucher disease) to the lysosome (Genetics Home Reference, 2003;Heybrock et al, 2019). Three zebrafish orthologues (scarb2a, b, c) correspond to SCARB2 (Frankish et al, 2017).…”