Nature communications, 2019-08, Vol.10 (1), p.3521-12, Article 3521
2019
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- Autor(en) / Beteiligte
- Titel
- Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export
- Ist Teil von
- Nature communications, 2019-08, Vol.10 (1), p.3521-12, Article 3521
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. Cholesterol transport is tightly regulated in the cell and in lysosomes is regulated by NPC1/2. Here, Heybrock et al. use molecular modeling, knockout mice and cell based studies to show that LIMP-2 also mediates lysosomal cholesterol transport.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-019-11425-0Titel-ID: cdi_doaj_primary_oai_doaj_org_article_7ad18a0cfcb742e09b108e2916ba4cfd
- Format
- –
- Schlagworte
- 14, 14/19, 14/28, 14/34, 14/35, 14/63, 631/45/287/1197, 631/80/642/1624, 64, 64/60, Animals, Carrier Proteins - genetics, Carrier Proteins - metabolism, CD36 Antigens - genetics, CD36 Antigens - metabolism, CHO Cells, Cholesterol, Cholesterol, LDL - metabolism, Cricetulus, Crosslinking, Depletion, Exports, Fibroblasts, Gene Knockout Techniques, HeLa Cells, Humanities and Social Sciences, Humans, Inclusions, Integral membrane proteins, Integrals, Intracellular Signaling Peptides and Proteins, Lipid Droplets - metabolism, Lipids, Low density lipoprotein, Lysosomal Membrane Proteins - genetics, Lysosomal Membrane Proteins - metabolism, Lysosomes, Lysosomes - metabolism, Membrane Glycoproteins - genetics, Membrane Glycoproteins - metabolism, Mice, Molecular modelling, multidisciplinary, Niemann-Pick C1 Protein, Protein Domains, Proteins, Receptors, Scavenger - genetics, Receptors, Scavenger - metabolism, RNA, Small Interfering - metabolism, Science, Science (multidisciplinary), Sterol regulatory element-binding protein, Thermophoresis, Transport