Departments of Bioengineering, McGill University, Montreal, QC H3A 0E9, Canada.
Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405.
Mol Biol Cell. 2022 Nov 1;33(13):ar128. doi: 10.1091/mbc.E22-01-0018. Epub 2022 Sep 21.
Microtubule-associated proteins (MAPs) modulate the motility of kinesin and dynein along microtubules to control the transport of vesicles and organelles. The neuronal MAP tau inhibits kinesin-dependent transport. Phosphorylation of tau at Tyr-18 by fyn kinase results in weakened inhibition of kinesin-1. We examined the motility of early endosomes and lysosomes in cells expressing wild-type (WT) tau and phosphomimetic Y18E tau. We quantified the effects on motility as a function of the tau expression level. Lysosome motility is strongly inhibited by tau. Y18E tau preferentially inhibits lysosomes in the cell periphery, while centrally located lysosomes are less affected. Early endosomes are more sensitive to tau than lysosomes and are inhibited by both WT and Y18E tau. Our results show that different cargoes have disparate responses to tau, likely governed by the types of kinesin motors driving their transport. In support of this model, kinesin-1 and -3 are strongly inhibited by tau while kinesin-2 and dynein are less affected. In contrast to kinesin-1, we find that kinesin-3 is strongly inhibited by phosphorylated tau.
微管相关蛋白 (MAPs) 调节驱动蛋白和动力蛋白沿微管的运动，以控制囊泡和细胞器的运输。神经元 MAP tau 抑制依赖于驱动蛋白的运输。fyn 激酶对 tau 的 Tyr-18 进行磷酸化导致对 kinesin-1 的抑制作用减弱。我们研究了表达野生型 (WT) tau 和磷酸模拟 Y18E tau 的细胞中的早期内体和溶酶体的运动。我们定量了运动作为 tau 表达水平的函数的影响。tau 强烈抑制溶酶体的运动。Y18E tau 优先抑制细胞外周的溶酶体，而中央定位的溶酶体受影响较小。早期内体比溶酶体对 tau 更敏感，WT 和 Y18E tau 都能抑制它们的运动。我们的结果表明，不同的货物对 tau 有不同的反应，这可能由驱动其运输的驱动蛋白的类型决定。支持该模型，tau 强烈抑制驱动蛋白-1 和 -3，而驱动蛋白-2 和动力蛋白受影响较小。与驱动蛋白-1 不同，我们发现磷酸化 tau 强烈抑制驱动蛋白-3。
