Sterols lower energetic barriers of membrane bending and fission necessary for efficient clathrin-mediated endocytosis.
Sterols lower energetic barriers of membrane bending and fission necessary for efficient clathrin-mediated endocytosis.
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DOI：
10.1016/j.celrep.2021.110008
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发表时间：
2021-11-16
期刊：
影响因子：
8.8
通讯作者：
Francis KR
中科院分区：
文献类型：
--
作者：
Anderson RH;Sochacki KA;Vuppula H;Scott BL;Bailey EM;Schultz MM;Kerkvliet JG;Taraska JW;Hoppe AD;Francis KR
细胞骨架蛋白介导的内吞作用(CME)在哺乳动物细胞的信号转导、受体循环和膜内稳态中起着至关重要的作用。胆固醇的急性耗竭扰乱了继续医学教育，在人类胆固醇代谢紊乱的背景下，激发了对继续医学教育动力学的分析。我们报告，抑制角鲨烯后胆固醇的生物合成会损害CME。膜弯曲动力学和CME凹坑超微结构的成像显示，网状蛋白凹坑寿命延长，并有浅的网状蛋白涂层结构，这表明曲率生成的进行性损害与甾醇丰度的减少有关。有效的CME的甾醇结构要求包括3‘极头基团和B-环构象，类似于紧密脂质堆积和极性的甾醇结构先决条件。此外，低胆固醇丰度的Smith-Lemli-Opitz成纤维细胞在CME介导的转铁蛋白内化方面存在缺陷。我们的结论是，在CME期间，甾醇降低了在凹坑形成和囊泡断裂过程中膜弯曲的能量成本，并提示CME活性降低可能有助于在胆固醇代谢障碍中观察到的细胞表型。Anderson et al.证明甾醇的丰度和特性在促进笼状蛋白介导的内吞作用中起主导作用。在内吞的多个阶段，对内吞多个阶段的细胞骨架蛋白包裹的凹坑的详细分析表明，在胆固醇代谢紊乱的发病机制中，内吞功能障碍是由类固醇介导的膜弯曲所必需的。
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. Anderson et al. demonstrate that sterol abundance and identity play a dominant role in facilitating clathrin-mediated endocytosis. Detailed analyses of clathrin-coated pits under sterol depletion support a requirement for sterol-mediated membrane bending during multiple stages of endocytosis, implicating endocytic dysfunction within the pathogenesis of disorders of cholesterol metabolism.
影响因子：
2
作者：
Cologna, Stephanie M.;Shieh, Christine;Toth, Cynthia L.;Cougnoux, Antony;Burkert, Kathryn R.;Bianconi, Simona E.;Wassif, Christopher A.;Porter, Forbes D.
通讯作者：
Porter, Forbes D.