Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol
Cells employ regulated transport mechanisms to ensure that their plasma membranes (PMs) are optimally supplied with cholesterol derived from uptake of low-density lipoproteins (LDL) and synthesis. To date, all inhibitors of cholesterol transport block steps in lysosomes, limiting our understanding o...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-04-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/25466 |
| _version_ | 1811235920205053952 |
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| author | Rodney Elwood Infante Arun Radhakrishnan |
| author_facet | Rodney Elwood Infante Arun Radhakrishnan |
| author_sort | Rodney Elwood Infante |
| collection | DOAJ |
| description | Cells employ regulated transport mechanisms to ensure that their plasma membranes (PMs) are optimally supplied with cholesterol derived from uptake of low-density lipoproteins (LDL) and synthesis. To date, all inhibitors of cholesterol transport block steps in lysosomes, limiting our understanding of post-lysosomal transport steps. Here, we establish the cholesterol-binding domain 4 of anthrolysin O (ALOD4) as a reversible inhibitor of cholesterol transport from PM to endoplasmic reticulum (ER). Using ALOD4, we: (1) deplete ER cholesterol without altering PM or overall cellular cholesterol levels; (2) demonstrate that LDL-derived cholesterol travels from lysosomes first to PM to meet cholesterol needs, and subsequently from PM to regulatory domains of ER to suppress activation of SREBPs, halting cholesterol uptake and synthesis; and (3) determine that continuous PM-to-ER cholesterol transport allows ER to constantly monitor PM cholesterol levels, and respond rapidly to small declines in cellular cholesterol by activating SREBPs, increasing cholesterol uptake and synthesis. |
| first_indexed | 2024-04-12T12:00:13Z |
| format | Article |
| id | doaj.art-5166bbad00a344dcaffc8a01d471e6a3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:00:13Z |
| publishDate | 2017-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5166bbad00a344dcaffc8a01d471e6a32022-12-22T03:33:52ZengeLife Sciences Publications LtdeLife2050-084X2017-04-01610.7554/eLife.25466Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterolRodney Elwood Infante0https://orcid.org/0000-0003-2605-822XArun Radhakrishnan1https://orcid.org/0000-0002-7266-7336Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States; Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United StatesDepartments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United StatesCells employ regulated transport mechanisms to ensure that their plasma membranes (PMs) are optimally supplied with cholesterol derived from uptake of low-density lipoproteins (LDL) and synthesis. To date, all inhibitors of cholesterol transport block steps in lysosomes, limiting our understanding of post-lysosomal transport steps. Here, we establish the cholesterol-binding domain 4 of anthrolysin O (ALOD4) as a reversible inhibitor of cholesterol transport from PM to endoplasmic reticulum (ER). Using ALOD4, we: (1) deplete ER cholesterol without altering PM or overall cellular cholesterol levels; (2) demonstrate that LDL-derived cholesterol travels from lysosomes first to PM to meet cholesterol needs, and subsequently from PM to regulatory domains of ER to suppress activation of SREBPs, halting cholesterol uptake and synthesis; and (3) determine that continuous PM-to-ER cholesterol transport allows ER to constantly monitor PM cholesterol levels, and respond rapidly to small declines in cellular cholesterol by activating SREBPs, increasing cholesterol uptake and synthesis.https://elifesciences.org/articles/25466cholesterol transportplasma membraneendoplasmic reticulumNiemann Pick Clysosomescholesterol-binding toxin |
| spellingShingle | Rodney Elwood Infante Arun Radhakrishnan Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol eLife cholesterol transport plasma membrane endoplasmic reticulum Niemann Pick C lysosomes cholesterol-binding toxin |
| title | Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol |
| title_full | Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol |
| title_fullStr | Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol |
| title_full_unstemmed | Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol |
| title_short | Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol |
| title_sort | continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol |
| topic | cholesterol transport plasma membrane endoplasmic reticulum Niemann Pick C lysosomes cholesterol-binding toxin |
| url | https://elifesciences.org/articles/25466 |
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