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Abstract
Sterols are crucial components of biological membranes, which are synthetized in the ER and accumulate in the plasma membrane (PM). Here, by applying a genetically encoded sterol biosensor (D4H), we visualize a sterol flow between PM and endosomes in the fission yeast Schizosaccharomyces pombe. Using time-lapse and correlative light-electron microscopy, we found that inhibition of Arp2/3-dependent F-actin assembly promotes the reversible relocalization of D4H from the PM to internal sterol-rich compartments (STRIC) labeled by synaptobrevin Syb1. Retrograde sterol internalization to STRIC is independent of endocytosis or an intact Golgi, but depends on Ltc1, a LAM/StARkin-family protein localized to ER-PM contact sites. The PM in ltc1Δ cells over-accumulates sterols and upon Arp2/3 inhibition forms extended ER-interacting invaginations, indicating that sterol transfer contributes to PM size homeostasis. Anterograde sterol movement from STRIC is independent of canonical vesicular trafficking but requires Arp2/3, suggesting a novel role for this complex. Thus, transfer routes orthogonal to vesicular trafficking govern the flow of sterols in the cell.
Highlights
Sterols are critical components of biological membranes with fundamental roles in cellular physiology
Sterols accumulate within the endosomal compartment upon Arp2/3 inhibition We examined the nature of the internal D4H-positive structures after 45 min Arp2/3 inhibition by correlative light-electron microscopy (CLEM)
We have used a genetically encoded fluorescent probe, D4H, to detect sterol-rich membranes in live cells, which revealed an intracellular sterol flux elicited upon Arp2/3 inhibition: sterols are carried from the plasma membrane (PM) to endosomes, likely through the ER, with the help of the lipid transfer protein Ltc1, and back to the PM independently of classical vesicular transport
Summary
Sterols are critical components of biological membranes with fundamental roles in cellular physiology. They confer essential biophysical properties to biomembranes, and regulate vesicular trafficking and signal transduction. They serve as precursors of hormones, bile acids, vitamin D, and energy storage molecules. Sterols are synthesized in the ER, their concentration within the ER does not exceed 0.5–1 mol% of total lipids (Luo et al, 2017). Instead, it increases along the secretory pathway, reaching ∼40 mol% at the plasma membrane (PM; Maxfield and van Meer, 2010). Within the PM, sterols cluster with other lipids, especially sphingolipids, forming membrane subdomains that range from the nanoscale to several micrometers (Alvarez et al, 2007; Makushok et al, 2016; Sezgin et al, 2017)
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