LET-767影响脂滴蛋白定位的作用机理研究

脂滴蛋白如何正确转移或定位到脂滴上发挥相应生物学功能是脂滴生物学领域的重要研究方向。目前关于脂滴蛋白定位的研究大多集中在鉴定脂滴蛋白自身的定位序列。我们利用秀丽线虫大规模遗传筛选优势，寻找调控脂滴蛋白定位的基因，发现RNAi干扰抑制HSD家族成员let-767表达，导致脂滴蛋白DHS-3、DGAT-2不能正确定位到脂滴，且脂滴变小，表明LET-767是一个新的影响脂滴蛋白定位、参与脂滴动态变化的蛋白，但作用机理未知。因此本项目将：1.在秀丽线虫、哺乳动物细胞系中多角度确认LET-767影响脂滴蛋白定位；2.LET-767直接或通过其他蛋白影响DHS-3、DGAT-2等脂滴蛋白定位的机制? 3.LET-767通过影响脂滴蛋白定位或其它因素影响脂滴增长的机制?本项目将对了解脂滴蛋白的脂滴定位及功能、脂滴增大和脂肪积累的调控机理，以及揭示脂代谢相关代谢性疾病发病机理，提供新的认识。

How lipid droplet (LD) protein is translocated to LD is one of key scientific questions in LD biology. Yet, most of studies on LD translocation focus on the targeting motifs of LD protein per se. Using the advantages of whole-genome screen in model organism C. elegans, we identified genes or proteins required for LD protein translocation and LD growth. We found that RNA interference (RNAi) of let-767, encoding a member of hydroxysteroid dehydrogenase (HSD), not only prevented LD growth but also remarkably impaired the LD translocation of DHS-3 and DGAT-2, two well-known LD proteins. In order to understand the underlying mechanisms of LET-767 in regulating LD growth and LD protein translocation, we proposed several research directions. First of all, we will further confirm whether LET-767 and its mammalian homologues play a conserved role for LD growth and LD protein localization. Secondly, how LET-767 directly or indirectly interacts with DHS-3 or DGAT-2 to determine their LD translocation and function. Thirdly, how LET-767 regulates LD growth and lipid accumulation via the DHS-3/DGAT-2 dependent or independent mechanism. Collectively, our research proposal will bring novel insights into the regulation of LD growth and LD proteins translocation appropriately, so as the pathogenesis of LD-related disorders.