Lysosomal Integral Membrane protein-2 (LIMP-2/SCARB2) Is Involved in Lysosomal Cholesterol Export

Nat Commun. 2019 Aug 6;10(1):3521. doi: 10.1038/s41467-019-11425-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD36 Antigens / genetics
  • CD36 Antigens / metabolism*
  • CHO Cells
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cholesterol, LDL / metabolism*
  • Cricetulus
  • Fibroblasts
  • Gene Knockout Techniques
  • HeLa Cells
  • Humans
  • Lipid Droplets / metabolism
  • Lysosome-Associated Membrane Glycoproteins / genetics
  • Lysosome-Associated Membrane Glycoproteins / metabolism*
  • Lysosomes / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Protein Domains
  • RNA, Small Interfering / metabolism
  • Receptors, Scavenger / genetics
  • Receptors, Scavenger / metabolism*

Substances

  • CD36 Antigens
  • Carrier Proteins
  • Cholesterol, LDL
  • Lysosome-Associated Membrane Glycoproteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • RNA, Small Interfering
  • Receptors, Scavenger
  • SCARB2 protein, human
  • Scarb2 protein, mouse

Grant support