Excess diacylglycerol at the endoplasmic reticulum disrupts endomembrane homeostasis and autophagy
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RESEARCH ARTICLE
Open Access
Excess diacylglycerol at the endoplasmic reticulum disrupts endomembrane homeostasis and autophagy Dan Li1, Shu-Gao Yang2, Cheng-Wen He1, Zheng-Tan Zhang1, Yongheng Liang3, Hui Li1, Jing Zhu1, Xiong Su2*, Qingqiu Gong1* and Zhiping Xie1*
Abstract Background: When 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. Results: Here, 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, ERaccumulated 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. Conclusions: This 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. Keywords: Phospholipid, Glycerolipid, Intracellular trafficking, Organelle, Autophagy
Background Lipids are essential building blocks of life. Polar lipids, including phospholipids, sphingolipids, and sterols, are major constituents of cellular membranes. Neutral lipids, in particular TAG, are employed as a storage medium of carbon nutrients [1, 2]. Storage lipid synthesis is induced * Correspondence: [email protected]; [email protected]; [email protected] 1 State Key Laboratory of Microbial Metabolism & Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, #800 Dong-Chuan Road, Shanghai 200240, People’s Republic of China 2 School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, People’s Republic of China Full list of author information is available at the end of the article
not only in the presence of nutrient surplus, but also in response to stress [3–6]. However, the amount of lipids that a cell or an organism can utilize and tolerate is limited. Too much lipid, from either environmental intake or de novo synthesis, can disrupt cellular homeostasis, leading to ER stress, ROS production, and cell death [7–9]. Recent studies revealed a close association of lipid metabolism with autophagy. Autophagy is
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