Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.

Proceedings of the National Academy of Sciences of the United States of America
Michael N TrinhFeiran Lu

Abstract

Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid-PS-controls the movement of another lipid-cholesterol-between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transp...Continue Reading

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Citations

Jan 10, 2021·Science China. Life Sciences·Jie LuoBao-Liang Song
Dec 31, 2020·Proceedings of the National Academy of Sciences of the United States of America·Xu XiaoPeter Tontonoz
Apr 22, 2021·The Journal of Cell Biology·Melina Casadio
May 2, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Tomoki Naito, Yasunori Saheki
Jun 5, 2021·Clinical Science·Diana Cardoso, Esperanza Perucha
Jun 13, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Valentin SchoopDoris Höglinger
Oct 1, 2021·Advanced Biology·Yvonne BaumerWilliam A Boisvert

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Methods Mentioned

BETA
fluorescence-activated cell sorting
flow cytometry
FCS
FACS
electrophoresis
Fluorescence Microscopy

Software Mentioned

MAGeCK

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