Journal
CELL REPORTS
Volume 37, Issue 7, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.110008
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Funding
- NIH [NIGMS P20 GM103620, P20 GM103548]
- National Science Foundation [0953561]
- National Science Foundation/EPSCoR Cooperative Agreement [IIA-1355423]
- State of South Dakota through BioSNTR, a South Dakota Research Innovation Center
- Intramural Research Program of the National Heart Lung and Blood Institute, National Institutes of Health [ZIA HL006098]
- National Institutes of Health under a Ruth L. Kirschstein Fellowship [F30 NS106788]
- Sanford Program for Undergraduate Research [P20 GM103620]
- University of South Dakota Center for Brain and Behavior Research
- Sanford Imaging core
- Sanford Flow Cytometry core
- NHLBI
- Div Of Biological Infrastructure
- Direct For Biological Sciences [0953561] Funding Source: National Science Foundation
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Clathrin-mediated endocytosis (CME) is crucial for cellular signal transduction, receptor recycling, and membrane homeostasis, while cholesterol depletion can disrupt CME; sterol structural requirements play an important role in efficient CME, and reduced cholesterol levels may contribute to defects in CME-mediated substance internalization.
Clathrin-mediated endocytosis (CME) is critical for cellular signal transduction, receptor recycling, and membrane homeostasis in mammalian cells. Acute depletion of cholesterol disrupts CME, motivating analysis of CME dynamics in the context of human disorders of cholesterol metabolism. We report that inhibition of post-squalene cholesterol biosynthesis impairs CME. Imaging of membrane bending dynamics and the CME pit ultrastructure reveals prolonged clathrin pit lifetimes and shallow clathrin-coated structures, suggesting progressive impairment of curvature generation correlates with diminishing sterol abundance. Sterol structural requirements for efficient CME include 3' polar head group and B-ring conformation, resembling the sterol structural prerequisites for tight lipid packing and polarity. Furthermore, Smith-Lemli-Opitz fibroblasts with low cholesterol abundance exhibit deficits in CME-mediated transferrin internalization. We conclude that sterols lower the energetic costs of membrane bending during pit formation and vesicular scission during CME and suggest that reduced CME activity may contribute to cellular phenotypes observed within disorders of cholesterol metabolism.
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