RAB18 Loss Interferes With Lipid Droplet Catabolism and Provokes Autophagy Network Adaptations
RAB18 Loss Interferes With Lipid Droplet Catabolism and Provokes Autophagy Network Adaptations
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DOI：
10.1016/j.jmb.2019.12.031
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发表时间：
2020-02-14
影响因子：
5.6
通讯作者：
Kern, Andreas
中科院分区：
文献类型：
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作者：
Bekbulat, Fazilet;Schmitt, Daniel;Kern, Andreas
自噬依赖于适当的脂质供应以形成自噬体。脂质获得的调节和自噬网络对脂质限制条件的反应大多是难以捉摸的。在这里，我们表明，敲除的RAB GT3 RAB 18干扰脂滴catalysts，导致受损的脂肪酸释放。由此产生的减少的脂滴衍生的脂质可用性影响自噬并引起自噬网络的适应性修改。这些调节包括增加ATG 2B的表达和磷酸化以及增加ATG 12-ATG 5缀合物的形成。此外，ATG 9A在氨基酸残基酪氨酸8和丝氨酸14处显示增强的磷酸化，导致增加的ATG 9A运输。通过药理学抑制Y8磷酸化，我们证明了这种ATG 9A修饰对于在RAB 18敲除条件下维持基础自噬是重要的。然而，虽然网络适应足以维持基础自噬活性，但它们不能确保饥饿时的自噬诱导，其特征在于增强的脂质需求。因此，在这里，我们定义了RAB 18在连接脂滴和自噬中的分子作用，强调脂滴作为降解途径的脂质来源的重要性，并揭示了显着的自噬网络可塑性，包括磷酸化依赖性ATG 9A激活，以补偿减少的脂质可用性，以挽救基础自噬活性。(C)2019作者（S）由爱思唯尔有限公司发布
Autophagy is dependent on appropriate lipid supply for autophagosome formation. The regulation of lipid acquisition and the autophagy network response to lipid-limiting conditions are mostly elusive. Here, we show that the knockout of the RAB GTPase RAB18 interferes with lipid droplet catabolism, causing an impaired fatty acid release. The resulting reduced lipid-droplet-derived lipid availability influences autophagy and provokes adaptive modifications of the autophagy network. These adjustments include increased expression and phosphorylation of ATG2B as well as augmented formation of the ATG12-ATG5 conjugate. Moreover, ATG9A shows an enhanced phosphorylation at amino acid residues tyrosine 8 and serine 14, resulting in an increased ATG9A trafficking. Via pharmacological inhibition of Y8 phosphorylation, we demonstrate that this ATG9A modification is important to maintain basal autophagy under RAB18 knockout conditions. However, while the network adaptations are sufficient to maintain basal autophagic activity, they are incapable of ensuring autophagy induction upon starvation, which is characterized by an enhanced lipid demand. Thus, here, we define the molecular role of RAB18 in connecting lipid droplets and autophagy, emphasize the significance of lipid droplets as lipid sources for the degradative pathway, and uncover a remarkable autophagy network plasticity, including phosphorylation-dependent ATG9A activation, to compensate reduced lipid availability in order to rescue basal autophagic activity. (C) 2019 The Author(s). Published by Elsevier Ltd.