Kumar Anita V, Mills Joslyn, Parker Wesley M, Leitão Joshua A, Rodriguez Diego I, Daigle Sandrine E, Ng Celeste, Patel Rishi, Aguilera Joseph L, Johnson Joseph R, Wong Shi Quan, Lapierre Louis R
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, USA.
Biology Department, Wheaton College, 26 E. Main Street, Norton, MA 02766, USA.
iScience. 2023 Sep 16;26(10):107960. doi: 10.1016/j.isci.2023.107960. eCollection 2023 Oct 20.
In several long-lived strains, such as insulin/IGF-1 receptor mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but their role in longevity is unclear. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we uncovered an important role for lipid droplets in proteostasis and longevity. Using genome-wide RNAi screening, we identified several SQST-1 modulators, including lipid droplets-associated and aggregation-prone proteins. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene enhanced autophagy, and extended lifespan. Notably, a substantial amount of ubiquitinated proteins were found on lipid droplets. Reducing lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised, and significantly reduced the lifespan of long-lived animals. Altogether, our study uncovered a key role for lipid droplets in as a proteostatic mediator that modulates ubiquitinated protein accumulation, facilitates autophagy, and promotes longevity.
在一些长寿品系中，如胰岛素/胰岛素样生长因子-1受体突变体，增强的蛋白质稳态机制伴随着肠道脂质储存的增加，但其在长寿中的作用尚不清楚。在这里，在确定选择性自噬受体SQST-1/SQSTM1的调控网络时，我们发现了脂滴在蛋白质稳态和长寿中的重要作用。通过全基因组RNA干扰筛选，我们鉴定了几种SQST-1调节剂，包括与脂滴相关且易于聚集的蛋白质。通过沉默保守的胞质三酰甘油脂肪酶基因来扩大肠道脂滴可增强自噬并延长寿命。值得注意的是，在脂滴上发现了大量泛素化蛋白。当自噬或蛋白酶体功能受损时，降低脂滴水平会加剧蛋白质稳态的崩溃，并显著缩短长寿动物的寿命。总之，我们的研究揭示了脂滴作为一种蛋白质稳态介质的关键作用，它调节泛素化蛋白的积累，促进自噬，并延长寿命。
