Abstract
Cholesterol is a major structural component of the plasma membrane (PM). The majority of PM cholesterol forms complexes with other PM lipids, making it inaccessible for intracellular transport. Transition of PM cholesterol between accessible and inaccessible pools maintains cellular homeostasis, but how cells monitor the accessibility of PM cholesterol remains unclear. We show that endoplasmic reticulum (ER)-anchored lipid transfer proteins, the GRAMD1s, sense and transport accessible PM cholesterol to the ER. GRAMD1s bind to one another and populate ER-PM contacts by sensing a transient expansion of the accessible pool of PM cholesterol via their GRAM domains. They then facilitate the transport of this cholesterol via their StART-like domains. Cells that lack all three GRAMD1s exhibit striking expansion of the accessible pool of PM cholesterol as a result of less efficient PM to ER transport of accessible cholesterol. Thus, GRAMD1s facilitate the movement of accessible PM cholesterol to the ER in order to counteract an acute increase of PM cholesterol, thereby activating non-vesicular cholesterol transport.
Highlights
Sterol is one of the major membrane lipids in eukaryotes
(Yeung et al, 2008), these results indicate that the recruitment of GRAMD1 proteins (GRAMD1s) to the plasma membrane (PM) is regulated by interactions between GRAM domains and anionic lipids, and that these interactions are enhanced by the additional presence of accessible/unsequestered cholesterol in the PM
As the total level of PM cholesterol was not elevated in GRAMD1 triple knockout (TKO) cells in our lipidomics analysis (Figure 4—figure supplement 3C,D), these results indicate that the chronic expansion of the accessible pool of PM cholesterol occurs in the absence of GRAMD1s
Summary
Cholesterol represents ~20% of total cellular lipids and is essential for the structural integrity of cellular membranes and for cell physiology (van Meer et al, 2008; Vance, 2015). Levels of sterol vary considerably between different cellular membranes. Between 60% and 80% of total cellular cholesterol is concentrated in the plasma membrane (PM), where it represents up to ~45% of total lipids in this bilayer (de Duve, 1971; Lange et al, 1989; Ray et al, 1969). Cellular cholesterol levels are maintained by regulated delivery and production, primarily through receptor-mediated endocytosis of low-density lipoproteins (LDLs) (Goldstein and Brown, 2015) and de novo synthesis in the endoplasmic reticulum (ER) that is controlled by the activation of SREBP transcription factors (Brown et al, 2018; Goldstein and Brown, 1990). Cholesterol is supplied to cells via high-density lipoproteins (HDL) through the reverse cholesterol flux pathway (Acton et al, 1996; Phillips, 2014)
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