Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France.
Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France.
Cell Death Differ. 2021 May;28(5):1733-1752. doi: 10.1038/s41418-020-00699-3. Epub 2020 Dec 17.
Oleate, the most abundant endogenous and dietary cis-unsaturated fatty acid, has the atypical property to cause the redistribution of microtubule-associated proteins 1A/1B light chain 3B (referred to as LC3) to the trans-Golgi network (TGN), as shown here. A genome-wide screen identified multiple, mostly Golgi transport-related genes specifically involved in the oleate-induced relocation of LC3 to the Golgi apparatus. Follow-up analyses revealed that oleate also caused the retention of secreted proteins in the TGN, as determined in two assays in which the secretion of proteins was synchronized, (i) an assay involving a thermosensitive vesicular stomatitis virus G (VSVG) protein that is retained in the endoplasmic reticulum (ER) until the temperature is lowered, and (ii) an isothermic assay involving the reversible retention of the protein of interest in the ER lumen and that was used both in vitro and in vivo. A pharmacological screen searching for agents that induce LC3 aggregation at the Golgi apparatus led to the identification of "oleate mimetics" that share the capacity to block conventional protein secretion. In conclusion, oleate represents a class of molecules that act on the Golgi apparatus to cause the recruitment of LC3 and to stall protein secretion.
油酸盐是最丰富的内源性和膳食顺式不饱和脂肪酸，具有将微管相关蛋白 1A/1B 轻链 3B（简称 LC3）重分布到反式高尔基体网络（TGN）的非典型特性，如这里所示。全基因组筛选鉴定出多个主要与高尔基体运输相关的基因，这些基因特异性地参与了 LC3 向高尔基体的再定位。后续分析表明，油酸盐还导致分泌蛋白在 TGN 中的滞留，这可以通过两种测定方法来确定，（i）一种测定方法涉及到一种热敏感的水疱性口炎病毒 G（VSVG）蛋白，该蛋白在温度降低之前被保留在内质网中，（ii）一种等温和测定方法涉及到感兴趣的蛋白在 ER 腔中的可逆保留，该方法既用于体外又用于体内。一种寻找在高尔基体处诱导 LC3 聚集的药物的药理学筛选导致了“油酸盐类似物”的鉴定，这些类似物具有阻断常规蛋白分泌的能力。总之，油酸盐代表了一类作用于高尔基体的分子，导致 LC3 的募集和蛋白分泌的停滞。
