Cholesterol in the cargo membrane amplifies tau inhibition of kinesin-1-based transport.
Cholesterol in the cargo membrane amplifies tau inhibition of kinesin-1-based transport.
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DOI：
10.1073/pnas.2212507120
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发表时间：
2023-01-17
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
在真核细胞中，驱动蛋白-1驱动囊泡沿沿着的长程运输。Tau对于微管组装和稳定是必不可少的，但封闭驱动蛋白结合位点。在细胞中，驱动蛋白通常通过流体脂质膜附着于囊泡货物。在这里，我们采用体外光捕获，以确定如何在tau蛋白的存在下，脂质货物膜影响驱动蛋白为基础的运输。我们发现，tau抑制驱动蛋白是由货物膜中的胆固醇调谐。我们的研究结果提供了深入了解驱动蛋白为基础的囊泡运输是如何保持在tau富集的条件下，如在神经元中发现的。此外，我们的研究结果确定货物膜胆固醇作为一个潜在的治疗目标，以减轻运输功能障碍，这是一个常见的早期标志的老化和神经退行性疾病。细胞内的货物往往被膜封闭，并在微管相关蛋白（MAP）的存在下，由微管为基础的马达运输。虽然越来越多的证据揭示了MAPs如何影响马达和微管之间的相互作用，但关于货物膜对运输的影响仍然存在关键问题。在这里，我们结合体外光捕获与理论方法，以确定在MAP tau的存在下，基于驱动蛋白的运输的脂质货物膜的效果。我们的研究结果表明，将驱动蛋白连接到流体脂质膜降低了tau蛋白对驱动蛋白的抑制作用。此外，添加胆固醇，这减少了驱动蛋白在货物膜中的扩散，以剂量依赖性方式放大了tau对驱动蛋白结合的抑制作用。我们提出，减少驱动蛋白扩散的货物膜的基础上的驱动蛋白结合在tau蛋白的存在下，胆固醇的影响，我们提供了一个简单的模型，这个建议的机制。我们的研究建立了货物膜胆固醇和基于MAP的驱动蛋白-1调控之间的直接联系。这里揭示的胆固醇效应可能更广泛地延伸到影响货物膜中运动扩散的其他脂质改变，包括与衰老和神经系统疾病相关的脂质改变。
Kinesin-1 drives long-range vesicle transport along microtubules in eukaryotic cells. Tau is essential for microtubule assembly and stabilization but occludes kinesin-binding sites. In cells, kinesins are often attached to vesicle cargos via a fluid lipid membrane. Here we employ in vitro optical trapping to determine how a lipid cargo membrane affects kinesin-based transport in the presence of tau. We show that tau-inhibition of kinesin is tuned by cholesterol in the cargo membrane. Our results provide insight into how kinesin-based vesicle transport is maintained under tau-enriched conditions such as those found in neurons. Moreover, our results identify cargo membrane cholesterol as a potential therapeutic target to mitigate transport dysfunctions that are a common early hallmark of aging and neurodegeneration. Intracellular cargos are often membrane-enclosed and transported by microtubule-based motors in the presence of microtubule-associated proteins (MAPs). Whereas increasing evidence reveals how MAPs impact the interactions between motors and microtubules, critical questions remain about the impact of the cargo membrane on transport. Here we combined in vitro optical trapping with theoretical approaches to determine the effect of a lipid cargo membrane on kinesin-based transport in the presence of MAP tau. Our results demonstrate that attaching kinesin to a fluid lipid membrane reduces the inhibitory effect of tau on kinesin. Moreover, adding cholesterol, which reduces kinesin diffusion in the cargo membrane, amplifies the inhibitory effect of tau on kinesin binding in a dosage-dependent manner. We propose that reduction of kinesin diffusion in the cargo membrane underlies the effect of cholesterol on kinesin binding in the presence of tau, and we provide a simple model for this proposed mechanism. Our study establishes a direct link between cargo membrane cholesterol and MAP-based regulation of kinesin-1. The cholesterol effects uncovered here may more broadly extend to other lipid alterations that impact motor diffusion in the cargo membrane, including those associated with aging and neurological diseases.
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DOI：
10.1126/science.1226734
发表时间：
2012-11-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Derr ND;Goodman BS;Jungmann R;Leschziner AE;Shih WM;Reck-Peterson SL
通讯作者：
Reck-Peterson SL
DOI：
10.1073/pnas.2021461118
发表时间：
2021-05-11
影响因子：
11.1
作者：
Gyparaki, Melina Theoni;Arab, Arian;Lakadamyali, Melike
通讯作者：
Lakadamyali, Melike
影响因子：
21.3
作者：
Coy, DL;Hancock, WO;Howard, J
通讯作者：
Howard, J
DOI：
10.1073/pnas.0510400103
发表时间：
2006-10-24
影响因子：
11.1
作者：
Kerssemakers, Jacob;Howard, Jonathon;Diez, Stefan
通讯作者：
Diez, Stefan
影响因子：
2
作者：
Carter, BC;Shubeita, GT;Gross, SP
通讯作者：
Gross, SP