CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, 08826, South Korea.
Department of Biophysics and Chemical Biology, Seoul National University, Seoul, 08826, South Korea.
Commun Biol. 2023 Mar 21;6(1):300. doi: 10.1038/s42003-023-04682-9.
Lipid droplets (LDs) are involved in various biological events in cells along with their primary role as a storage center for neutral lipids. Excessive accumulation of LDs is highly correlated with various diseases, including metabolic diseases. Therefore, a basic understanding of the molecular mechanism of LD degradation would be beneficial in both academic and industrial research. Lipophagy, a selective autophagy mechanism/LD degradation process, has gained increased attention in the research community. Herein, we sought to elucidate a novel lipophagy mechanism by utilizing the LD-degrading small molecule, SB2301, which activates ubiquitin-mediated lipophagy. Using a label-free target identification method, we revealed that ethanolamine-phosphate cytidylyltransferase 2 (PCYT2) is a potential target protein of SB2301. We also demonstrated that although SB2301 does not modulate PCYT2 function, it induces the cellular translocation of PCYT2 to the LD surface and spatially increases the phosphatidylethanolamine (PE)/phosphatidylcholine (PC) ratio of the LD membrane, causing LD coalescence, leading to the activation of lipophagy process to maintain energy homeostasis.
脂滴（LDs）在细胞中参与各种生物事件，其主要作用是作为中性脂质的储存中心。LD 的过度积累与各种疾病高度相关，包括代谢疾病。因此，深入了解 LD 降解的分子机制在学术和工业研究中都将是有益的。噬脂作用（lipophagy），一种选择性自噬机制/LD 降解过程，在研究界受到了越来越多的关注。在这里，我们试图利用 LD 降解小分子 SB2301 阐明一种新的噬脂作用机制，该小分子通过激活泛素介导的噬脂作用来促进 LD 降解。我们使用无标记靶标鉴定方法发现乙醇胺磷酸胞苷转移酶 2（PCYT2）是 SB2301 的潜在靶标蛋白。我们还证明，尽管 SB2301 不调节 PCYT2 的功能，但它诱导 PCYT2 向 LD 表面的细胞易位，并在空间上增加 LD 膜的磷脂酰乙醇胺（PE）/磷脂酰胆碱（PC）比率，导致 LD 融合，从而激活噬脂作用过程以维持能量平衡。
