Faculté de Pharmacie, University Paris-Sud 11, JE 2493, IFR141, Châtenay-Malabry, France.
J Biol Chem. 2010 Jul 30;285(31):24184-94. doi: 10.1074/jbc.M109.091553. Epub 2010 May 18.
The molecular mechanisms underlying microtubule participation in autophagy are not known. In this study, we show that starvation-induced autophagosome formation requires the most dynamic microtubule subset. Upon nutrient deprivation, labile microtubules specifically recruit markers of autophagosome formation like class III-phosphatidylinositol kinase, WIPI-1, the Atg12-Atg5 conjugate, and LC3-I, whereas mature autophagosomes may bind to stable microtubules. We further found that upon nutrient deprivation, tubulin acetylation increases both in labile and stable microtubules and is required to allow autophagy stimulation. Tubulin hyperacetylation on lysine 40 enhances kinesin-1 and JIP-1 recruitment on microtubules and allows JNK phosphorylation and activation. JNK, in turn, triggers the release of Beclin 1 from Bcl-2-Beclin 1 complexes and its recruitment on microtubules where it may initiate autophagosome formation. Finally, although kinesin-1 functions to carry autophagosomes in basal conditions, it is not involved in motoring autophagosomes after nutrient deprivation. Our results show that the dynamics of microtubules and tubulin post-translational modifications play a major role in the regulation of starvation-induced autophagy.
微管参与自噬的分子机制尚不清楚。在本研究中，我们表明饥饿诱导的自噬体形成需要最具动态性的微管亚群。在营养剥夺时，不稳定微管特异性募集自噬体形成的标志物，如 III 型磷酸肌醇激酶、WIPI-1、Atg12-Atg5 缀合物和 LC3-I，而成熟的自噬体可能与稳定的微管结合。我们进一步发现，在营养剥夺时，不稳定和稳定微管中的微管蛋白乙酰化均增加，这对于允许自噬刺激是必需的。微管蛋白赖氨酸 40 上的乙酰化增强了驱动蛋白-1 和 JIP-1 在微管上的募集，并允许 JNK 磷酸化和激活。JNK 反过来触发 Beclin 1 从 Bcl-2-Beclin 1 复合物中的释放，并将其募集到微管上，在微管上它可能启动自噬体的形成。最后，虽然驱动蛋白-1在基础条件下作用于携带自噬体，但它不参与营养剥夺后自噬体的运动。我们的结果表明，微管的动力学和微管蛋白的翻译后修饰在饥饿诱导的自噬调控中起着主要作用。
