Excess diacylglycerol at the endoplasmic reticulum disrupts endomembrane homeostasis and autophagy
Excess diacylglycerol at the endoplasmic reticulum disrupts endomembrane homeostasis and autophagy
复制标题
内质网过量的二酰甘油会破坏内膜稳态和自噬
DOI：
10.1186/s12915-020-00837-w
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发表时间：
2020-08-28
期刊：
影响因子：
5.4
通讯作者：
Xie, Zhiping
中科院分区：
文献类型：
--
作者：
Li, Dan;Yang, Shu-Gao;Xie, Zhiping
研究背景真核细胞在应激时产生三酰甘油（TAG）来储存营养物质，并通过自噬来对抗内部损伤。我们和其他人以前曾报道，在酵母中，消除TAG合成酶抑制自噬氮饥饿下，但潜在的机制仍然habitu.ResultsHere，我们表明，TAG合成中断导致甘油二酯（DAG）的积累和搬迁从空泡膜的内质网（ER）。我们进一步表明，除了自噬，ER积累的DAG引起内膜系统的严重缺陷，包括扰乱ER-高尔基体蛋白运输的平衡，表现在ER的膨胀和高尔基体的损失。增加DAG消耗或减少DAG供应的遗传或化学操作逆转了这些缺陷。相反，增加量的前体的甘油脂质合成，包括磷脂酸和游离脂肪酸，没有复制的影响，过量的DAG。我们还提供了证据表明，所观察到的内膜缺陷不依赖于高尔基体产生的DAG，Pkc 1信号，或未折叠的蛋白response.ConclusionsThis工作确定DAG作为关键的脂质分子负责自噬抑制的条件下，有缺陷的TAG合成，并证明ER和高尔基体功能的破坏过量DAG作为自噬缺陷的潜在原因。
BackgroundWhen stressed, eukaryotic cells produce triacylglycerol (TAG) to store nutrients and mobilize autophagy to combat internal damage. We and others previously reported that in yeast, elimination of TAG synthesizing enzymes inhibits autophagy under nitrogen starvation, yet the underlying mechanism has remained elusive.ResultsHere, we show that disruption of TAG synthesis led to diacylglycerol (DAG) accumulation and its relocation from the vacuolar membrane to the endoplasmic reticulum (ER). We further show that, beyond autophagy, ER-accumulated DAG caused severe defects in the endomembrane system, including disturbing the balance of ER-Golgi protein trafficking, manifesting in bulging of ER and loss of the Golgi apparatus. Genetic or chemical manipulations that increase consumption or decrease supply of DAG reversed these defects. In contrast, increased amounts of precursors of glycerolipid synthesis, including phosphatidic acid and free fatty acids, did not replicate the effects of excess DAG. We also provide evidence that the observed endomembrane defects do not rely on Golgi-produced DAG, Pkc1 signaling, or the unfolded protein response.ConclusionsThis work identifies DAG as the critical lipid molecule responsible for autophagy inhibition under condition of defective TAG synthesis and demonstrates the disruption of ER and Golgi function by excess DAG as the potential cause of the autophagy defect.