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Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol

Infante, Rodney Elwood, Radhakrishnan, Arun·2017·eLife
DOI 10.7554/elife.25466PMC PMC5433840
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Abstract

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.

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  • Treatment with sphingomyelinase releases cholesterol from sphingomyelin, thereby increasing the accessible pool.

    “Treatment with sphingomyelinase releases cholesterol from sphingomyelin, thereby increasing the accessible pool.”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [8]

    The Introduction (page not provided) says sphingomyelin sequesters a pool of plasma-membrane cholesterol and distinguishes it from accessible cholesterol. It does not say that sphingomyelinase treatment releases that cholesterol or increases the accessible pool; a search for sphingomyelinase found no passage describing that treatment. (LLM, conf=0.82)

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  • PM cholesterol exists in three pools: an accessible pool, a sphingomyelin-bound inaccessible pool, and a third inaccessible pool essential for cell viability.

    “PM cholesterol exists in three pools (7). One pool is termed “accessible” because its cholesterol is accessible to the cholesterol-binding toxins PFO* and anthrolysin O (7, 8). A second pool is bound to sphingomyelin and thus is inaccessible to these toxins. The third pool is also inaccessible and is essential for cell viability (7).”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [8]

    The Introduction (page unavailable) describes three PM cholesterol pools: one sequestered by sphingomyelin, another sequestered by other membrane factors, and an excess pool accessible to cholesterol-binding PFO. This supports the three-pool distinction, but the cited passage does not say that the other inaccessible pool is essential for cell viability. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Other widely used toxin-based biosensors for accessible cholesterol, including D4 of ALO and PFO, are useful for measuring levels of accessible cholesterol in the PM, but they trap accessible cholesterol in the PM and induce dysregulation of cholesterol homeostasis.

    “Other widely used toxin‐based biosensors for accessible cholesterol, including D4 of ALO and PFO, are useful for measuring levels of accessible cholesterol in the PM, but they trap accessible cholesterol in the PM and induce dysregulation of cholesterol homeostasis (Infante & Radhakrishnan, 2017; Johnson et al, 2019).”

    From Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b (2021) · cites this paper as Infante & Radhakrishnan, 2017

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • LDL-derived cholesterol travels from lysosomes to the plasma membrane before moving to the ER.

    “studies with cholesterol-binding toxins have provided evidence that LDL-derived cholesterol travels from lysosomes to the PM before moving to the ER (7, 8).”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [8]

  • The accessible pool of cholesterol is the only pool that is free to move to the ER to exert regulatory actions.

    “The accessible pool of cholesterol is the only pool that is free to move to the ER to exert regulatory actions (7, 8, 29).”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [8]

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Metadata

Authors
Infante, R. E., & Radhakrishnan, A.
Affiliations
Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2017-04-17
Volume
6
ISSN
2050-084X
DOI
10.7554/elife.25466
PMC
PMC5433840
Cited by
163
References
5
Language
en
Licence
Funders
  • National Institutes of Health (HL20948, T32DK007745)
  • Welch Foundation (I-1793)
  • American Heart Association (12SDG12040267)

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