Cargando…
Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol
Low-density lipoprotein (LDL) delivers cholesterol to mammalian cells through receptor-mediated endocytosis. The LDL cholesterol is liberated in lysosomes and transported to the plasma membrane (PM) and from there to the endoplasmic reticulum (ER). Excess ER cholesterol is esterified with a fatty ac...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764668/ https://www.ncbi.nlm.nih.gov/pubmed/34992143 http://dx.doi.org/10.1073/pnas.2120411119 |
_version_ | 1784634214261456896 |
---|---|
author | Trinh, Michael N. Brown, Michael S. Seemann, Joachim Vale, Gonçalo McDonald, Jeffrey G. Goldstein, Joseph L. Lu, Feiran |
author_facet | Trinh, Michael N. Brown, Michael S. Seemann, Joachim Vale, Gonçalo McDonald, Jeffrey G. Goldstein, Joseph L. Lu, Feiran |
author_sort | Trinh, Michael N. |
collection | PubMed |
description | Low-density lipoprotein (LDL) delivers cholesterol to mammalian cells through receptor-mediated endocytosis. The LDL cholesterol is liberated in lysosomes and transported to the plasma membrane (PM) and from there to the endoplasmic reticulum (ER). Excess ER cholesterol is esterified with a fatty acid for storage as cholesteryl esters. Recently, we showed that PM-to-ER transport of LDL cholesterol requires phosphatidylserine (PS). Others showed that PM-to-ER transport of cholesterol derived from other sources requires Asters (also called GRAMD1s), a family of three ER proteins that bridge between the ER and PM by binding to PS. Here, we use a cholesterol esterification assay and other measures of ER cholesterol delivery to demonstrate that Asters participate in PM-to-ER transport of LDL cholesterol in Chinese hamster ovary cells. Knockout of the gene encoding PTDSS1, the major PS-synthesizing enzyme, lowered LDL-stimulated cholesterol esterification by 85%, whereas knockout of all three Aster genes lowered esterification by 65%. The reduction was even greater (94%) when the genes encoding PTDSS1 and the three Asters were knocked out simultaneously. We conclude that Asters participate in LDL cholesterol delivery from PM to ER, and their action depends in large part, but not exclusively, on PS. The data also indicate that PS participates in another delivery pathway, so far undefined, that is independent of Asters. |
format | Online Article Text |
id | pubmed-8764668 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-87646682022-01-26 Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol Trinh, Michael N. Brown, Michael S. Seemann, Joachim Vale, Gonçalo McDonald, Jeffrey G. Goldstein, Joseph L. Lu, Feiran Proc Natl Acad Sci U S A Biological Sciences Low-density lipoprotein (LDL) delivers cholesterol to mammalian cells through receptor-mediated endocytosis. The LDL cholesterol is liberated in lysosomes and transported to the plasma membrane (PM) and from there to the endoplasmic reticulum (ER). Excess ER cholesterol is esterified with a fatty acid for storage as cholesteryl esters. Recently, we showed that PM-to-ER transport of LDL cholesterol requires phosphatidylserine (PS). Others showed that PM-to-ER transport of cholesterol derived from other sources requires Asters (also called GRAMD1s), a family of three ER proteins that bridge between the ER and PM by binding to PS. Here, we use a cholesterol esterification assay and other measures of ER cholesterol delivery to demonstrate that Asters participate in PM-to-ER transport of LDL cholesterol in Chinese hamster ovary cells. Knockout of the gene encoding PTDSS1, the major PS-synthesizing enzyme, lowered LDL-stimulated cholesterol esterification by 85%, whereas knockout of all three Aster genes lowered esterification by 65%. The reduction was even greater (94%) when the genes encoding PTDSS1 and the three Asters were knocked out simultaneously. We conclude that Asters participate in LDL cholesterol delivery from PM to ER, and their action depends in large part, but not exclusively, on PS. The data also indicate that PS participates in another delivery pathway, so far undefined, that is independent of Asters. National Academy of Sciences 2022-01-06 2022-01-11 /pmc/articles/PMC8764668/ /pubmed/34992143 http://dx.doi.org/10.1073/pnas.2120411119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Trinh, Michael N. Brown, Michael S. Seemann, Joachim Vale, Gonçalo McDonald, Jeffrey G. Goldstein, Joseph L. Lu, Feiran Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol |
title | Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol |
title_full | Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol |
title_fullStr | Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol |
title_full_unstemmed | Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol |
title_short | Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol |
title_sort | interplay between asters/gramd1s and phosphatidylserine in intermembrane transport of ldl cholesterol |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764668/ https://www.ncbi.nlm.nih.gov/pubmed/34992143 http://dx.doi.org/10.1073/pnas.2120411119 |
work_keys_str_mv | AT trinhmichaeln interplaybetweenastersgramd1sandphosphatidylserineinintermembranetransportofldlcholesterol AT brownmichaels interplaybetweenastersgramd1sandphosphatidylserineinintermembranetransportofldlcholesterol AT seemannjoachim interplaybetweenastersgramd1sandphosphatidylserineinintermembranetransportofldlcholesterol AT valegoncalo interplaybetweenastersgramd1sandphosphatidylserineinintermembranetransportofldlcholesterol AT mcdonaldjeffreyg interplaybetweenastersgramd1sandphosphatidylserineinintermembranetransportofldlcholesterol AT goldsteinjosephl interplaybetweenastersgramd1sandphosphatidylserineinintermembranetransportofldlcholesterol AT lufeiran interplaybetweenastersgramd1sandphosphatidylserineinintermembranetransportofldlcholesterol |