The insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in Caenorhabditis elegans.
The insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in Caenorhabditis elegans.
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DOI：
10.7554/elife.38635
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发表时间：
2018-11-07
期刊：
影响因子：
7.7
通讯作者：
Cohen E
中科院分区：
文献类型：
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作者：
Moll L;Roitenberg N;Bejerano-Sagie M;Boocholez H;Carvalhal Marques F;Volovik Y;Elami T;Siddiqui AA;Grushko D;Biram A;Lampert B;Achache H;Ravid T;Tzur YB;Cohen E
虽然衰老调节途径在几十年前就被发现了，但人们并不完全清楚它们的活动是如何被精心安排的，如何在生物体水平上控制寿命和蛋白质平衡。在这里，我们利用秀丽隐杆线虫来研究衰老的改变是否通过降低胰岛素/IGF信号（IIS）级联的活性来影响蛋白质sumo化。我们发现IIS的活性促进了种系蛋白CAR-1的sumo化，从而缩短了寿命并损害了蛋白质平衡。相反，在残基185处不能被SUMOylated的突变CAR-1的表达延长了寿命并增强了蛋白质的稳态。一项机制分析表明，CAR-1至少部分通过缺口样受体glp-1介导其衰老改变功能。我们的发现揭示了一个新的调控轴，其中SUMOylation被用来整合IIS和种系的衰老控制功能，并为SUMOylation在调节机体衰老中的作用提供了新的见解。衰老似乎是不可避免的，但有许多因素，从饮食到基因突变，都会影响这一过程。事实上，科学家们已经开始揭示控制和影响这种缓慢下降的机制。例如，在秀丽隐杆线虫（Caenorhabditis elegans）中，去除产生卵子的细菌细胞可以延长其寿命。同样，干扰胰岛素/IGF-1信号通路（IIS）的活性可以延长动物的寿命。然而，目前尚不清楚这两种机制是协同工作，还是并行工作。为了探索这一点，Moll， Roitenberg等人首先研究了IIS途径如何调节秀丽隐杆线虫中一种被称为SUMOylation的蛋白质修饰。降低IIS通路的活性可以减缓蠕虫的衰老。它还降低了某些蛋白质的sumo酰化水平，包括在产生生殖细胞的结构中发现的CAR-1。进一步的实验表明，停止CAR-1的sumo化可以延长动物的寿命。事实上，用不能接受SUMO元素的CAR-1突变版本取代这种蛋白质，可以使蠕虫活得更长，并抵抗一种导致人类阿尔茨海默病的有毒蛋白质。因此，这些结果表明，在秀丽隐杆线虫中，IIS途径和生殖细胞中涉及CAR-1的机制共同决定了衰老的速度。现在需要进一步的研究来剖析IIS途径如何影响SUMOylation，以及这些发现是否适用于哺乳动物。
Although aging-regulating pathways were discovered a few decades ago, it is not entirely clear how their activities are orchestrated, to govern lifespan and proteostasis at the organismal level. Here, we utilized the nematode Caenorhabditis elegans to examine whether the alteration of aging, by reducing the activity of the Insulin/IGF signaling (IIS) cascade, affects protein SUMOylation. We found that IIS activity promotes the SUMOylation of the germline protein, CAR-1, thereby shortening lifespan and impairing proteostasis. In contrast, the expression of mutated CAR-1, that cannot be SUMOylated at residue 185, extends lifespan and enhances proteostasis. A mechanistic analysis indicated that CAR-1 mediates its aging-altering functions, at least partially, through the notch-like receptor glp-1. Our findings unveil a novel regulatory axis in which SUMOylation is utilized to integrate the aging-controlling functions of the IIS and of the germline and provide new insights into the roles of SUMOylation in the regulation of organismal aging. Aging may seem inescapable, but there are many factors, from diet to genetic mutations, that can affect this process. In fact, scientists have started to uncover the mechanisms that control and influence this slow decline. For example, in the small worm Caenorhabditis elegans, removing the germs cells – which give rise to eggs – extends the lifespan. Similarly, interfering with the activity of the Insulin/IGF-1 signaling (IIS) pathway leads to a longer life for the animals. However, it is unclear whether these two mechanisms work together, or if they operate in parallel. To explore this, Moll, Roitenberg et al. first looked at how the IIS pathway regulates a type of protein modification known as SUMOylation in C. elegans. Reducing the activity of the IIS pathway slowed down aging in the worms. It also decreased the levels of SUMOylation of certain proteins, including CAR-1, which is found in the structures that produce germ cells. Further experiments showed that stopping the SUMOylation of CAR-1 extended the lifespan of the animals. In fact, replacing the protein with a mutated version of CAR-1 that cannot accept the SUMO element makes the worms live longer and resist a toxic protein that causes Alzheimer’s disease in humans. These results therefore show that, in C. elegans, the IIS pathway and a mechanism that involves CAR-1 in germ cells work together to determine the pace of aging. Further studies are now needed to dissect how the IIS pathway influences SUMOylation, and whether the findings hold true in mammals.