Speer Natalie Ortiz, Braun Randolph Jay, Reynolds Emma, Brudnicka Alicja, Swanson Jessica, Henne W Mike
bioRxiv. 2023 Sep 11:2023.03.07.531595. doi: 10.1101/2023.03.07.531595.
Cells store lipids in the form of triglyceride (TG) and sterol-ester (SE) in lipid droplets (LDs). Distinct pools of LDs exist, but a pervasive question is how proteins localize to and convey functions to LD subsets. Here, we show the yeast protein YDR275W/Tld1 (for TG-associated LD protein 1) localizes to a subset of TG-containing LDs, and reveal it negatively regulates lipolysis. Mechanistically, Tld1 LD targeting requires TG, and is mediated by two distinct hydrophobic regions (HRs). Molecular dynamics simulations reveal Tld1 HRs interact with TG on LDs and adopt specific conformations on TG-rich LDs versus SE-rich LDs in yeast and human cells. Tld1-deficient yeast display no defect in LD biogenesis, but exhibit elevated TG lipolysis dependent on lipase Tgl3. Remarkably, over-expression of Tld1, but not LD protein Pln1/Pet10, promotes TG accumulation without altering SE pools. Finally, we find Tld1-deficient cells display altered LD mobilization during extended yeast starvation. We propose Tld1 senses TG-rich LDs and regulates lipolysis on LD subpopulations.
细胞以甘油三酯（TG）和固醇酯（SE）的形式将脂质储存在脂滴（LD）中。存在不同的脂滴库，但一个普遍存在的问题是蛋白质如何定位于脂滴亚群并向其传递功能。在这里，我们表明酵母蛋白YDR275W/Tld1（与TG相关的脂滴蛋白1）定位于含TG的脂滴亚群，并揭示其对脂解具有负调控作用。从机制上讲，Tld1靶向脂滴需要TG，并由两个不同的疏水区域（HR）介导。分子动力学模拟表明，Tld1的HR与脂滴上的TG相互作用，并在酵母和人类细胞中富含TG的脂滴与富含SE的脂滴上呈现特定构象。缺乏Tld1的酵母在脂滴生物合成方面没有缺陷，但依赖于脂肪酶Tgl3表现出TG脂解增加。值得注意的是，Tld1的过表达，而不是脂滴蛋白Pln1/Pet10的过表达，促进了TG的积累而不改变SE库。最后，我们发现缺乏Tld1的细胞在酵母长期饥饿期间脂滴动员发生改变。我们提出Tld1感知富含TG的脂滴并调节脂滴亚群上的脂解。
