Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans.
Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans.
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DOI：
10.1016/j.isci.2023.107960
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发表时间：
2023-10-20
期刊：
影响因子：
5.8
通讯作者：
Lapierre, Louis R.
中科院分区：
文献类型：
--
作者：
V. Kumar, Anita;Mills, Joslyn;Parker, Wesley M.;Leitao, Joshua A.;Rodriguez, Diego I.;Daigle, Sandrine E.;Ng, Celeste;Patel, Rishi;Aguilera, Joseph L.;Johnson, Joseph R.;Wong, Shi Quan;Lapierre, Louis R.
在一些长寿的秀丽隐杆线虫菌株中，如胰岛素/IGF-1受体daf-2突变体，增强的蛋白抑制机制伴随着肠道脂质储存的增加，但它们在长寿中的作用尚不清楚。本研究在确定选择性自噬受体SQST-1/SQSTM1的调控网络的同时，揭示了脂滴在蛋白质停滞和长寿中的重要作用。通过全基因组RNAi筛选，我们确定了几种SQST-1调节剂，包括脂滴相关蛋白和易聚集蛋白。通过沉默保守的胞质三酰基甘油脂肪酶基因ATGL -1/ATGL来扩大肠道脂滴，增强自噬，延长寿命。值得注意的是，在脂滴上发现了大量的泛素化蛋白。当自噬或蛋白酶体功能受损时，脂滴水平的降低加剧了蛋白酶抑制作用的崩溃，并显著降低了长寿daf-2动物的寿命。总之，我们的研究揭示了秀丽隐杆线虫中脂滴作为一种蛋白质抑制介质的关键作用，它可以调节泛素化蛋白的积累，促进自噬，并延长寿命。低脂储存挑战了SQST-1促进蛋白质降解的能力，高脂滴含量稳定了易聚集的蛋白质，脂滴可以缓解年龄相关的蛋白质抑制能力下降。生物化学
In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 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 atgl-1/ATGL 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 daf-2 animals. Altogether, our study uncovered a key role for lipid droplets in C. elegans as a proteostatic mediator that modulates ubiquitinated protein accumulation, facilitates autophagy, and promotes longevity. Elevated levels of SQST-1/SQSTM1 are detrimental to lifespan in C. elegans Low lipid stores challenge the ability of SQST-1 to facilitate protein degradation High lipid droplet content stabilizes aggregation-prone proteins Age-related proteostatic decline is mitigated by lipid droplets Biological sciences; Biochemistry
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影响因子：
20.8
作者：
Ding L;Sun W;Balaz M;He A;Klug M;Wieland S;Caiazzo R;Raverdy V;Pattou F;Lefebvre P;Lodhi IJ;Staels B;Heim M;Wolfrum C
通讯作者：
Wolfrum C
影响因子：
8.8
作者：
Dhondt I;Petyuk VA;Cai H;Vandemeulebroucke L;Vierstraete A;Smith RD;Depuydt G;Braeckman BP
通讯作者：
Braeckman BP
影响因子：
3.7
作者：
Brooks KK;Liang B;Watts JL
通讯作者：
Watts JL
影响因子：
13.3
作者：
Demishtein, Alik;Fraiberg, Milana;Navon, Ami
通讯作者：
Navon, Ami
DOI：
10.1073/pnas.1413706111
发表时间：
2014-10-14
影响因子：
11.1
作者：
Inloes, Jordon M.;Hsu, Ku-Lung;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.