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.
Autophagy. 2021 Mar;17(3):820-822. doi: 10.1080/15548627.2020.1861836. Epub 2020 Dec 23.
Oleate, the most abundantly occurring -unsaturated fatty acid, has the particularity to induce the accumulation of MAP1LC3B/LC3 (microtubule associated protein 1 light chain 3 beta) at the -Golgi apparatus. A genome-wide RNA interference screen designed to identify the mechanisms of this LC3 redistribution led to the identification of a BECN1-PIK3C3-independent pathway that, however, requires the ATG12-ATG5 and ATG7-dependent conjugation system, and several genes/proteins involved in endoplasmic reticulum (ER)-to-Golgi anterograde protein transport, as well as the unfolded protein response, including the integrated stress response that results in the phosphorylation of EIF2A/eIF2α (eukaryotic translation initiation factor 2A). Functional experiments revealed that oleate blocks conventional protein secretion, stalling the process at the level of the -Golgi network. Oleate-induced blockade of protein secretion occurred even after depletion of ATG5, suggesting that it does not rely on the recruitment of LC3 to the Golgi apparatus (which does require ATG5). Rather, it appears that oleate and other pharmacological inhibitors of protein secretion with a similar mode of action provoke a perturbation of the -Golgi compartment that secondarily results in the local enrichment of LC3.
油酸盐是最丰富的 - 不饱和脂肪酸，其特点是诱导 MAP1LC3B/LC3（微管相关蛋白 1 轻链 3β）在 - 高尔基体上的积累。一个旨在识别这种 LC3 重分布机制的全基因组 RNA 干扰筛选导致了一种 BECN1-PIK3C3 独立的途径的鉴定，然而，该途径需要 ATG12-ATG5 和 ATG7 依赖性缀合系统，以及几个涉及内质网（ER）-高尔基体顺行蛋白运输的基因/蛋白，以及未折叠蛋白反应，包括导致 EIF2A/eIF2α（真核翻译起始因子 2A）磷酸化的整合应激反应。功能实验表明，油酸盐阻断常规蛋白分泌，使过程在 - 高尔基体网络水平停滞。即使在耗尽 ATG5 后，油酸盐诱导的蛋白分泌阻断仍然发生，这表明它不依赖于 LC3 向高尔基体的募集（这确实需要 ATG5）。相反，油酸盐和其他具有类似作用模式的蛋白分泌药理学抑制剂似乎会引起 - 高尔基体隔室的扰动，从而导致 LC3 的局部富集。
