Genetic regulation of Caenorhabditis elegans lysosome related organelle function.
Genetic regulation of Caenorhabditis elegans lysosome related organelle function.
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DOI：
10.1371/journal.pgen.1003908
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发表时间：
2013-10
期刊：
影响因子：
4.5
通讯作者：
Ruvkun G
中科院分区：
文献类型：
--
作者：
Soukas AA;Carr CE;Ruvkun G
溶酶体是膜结合的细胞器，其含有降解细胞蛋白质、脂质、核酸和寡糖的酸水解酶，并且对于细胞维持和保护免受年龄相关衰退是重要的。溶酶体相关细胞器（LRO）是从人类到蠕虫的生物体中发现的特化溶酶体，并且具有许多经典溶酶体的特征。缺陷的LRO与人类免疫紊乱和神经系统疾病有关。秀丽隐杆线虫LRO是活性染料如尼罗红以及与年龄相关的自发荧光的浓缩部位。尽管某些短寿命突变体具有高LRO尼罗红和高自体荧光，而其他长寿命突变体具有低LRO尼罗红和低自体荧光，但这两种生物制剂是不同的。我们确定了一个通过5-羟色胺信号和编码线粒体酮硫解酶的基因kat-1调节衰老相关LRO表型的遗传途径。5-羟色胺和kat-1对LRO表型的调节反过来取决于质子偶联的跨膜转运蛋白SKAT-1。skat-1功能缺失突变强烈抑制kat-1突变的高LRO尼罗红积累表型。使用系统方法，我们进一步分析了571个基因在LRO生物学中的作用。这些结果突出了一个基因网络，调节LRO生物学的方式依赖于保守的蛋白激酶TOR复合物2。这些结果暗示了LRO生物学、衰老相关生理学和潜在的LRO人类疾病中涉及的新遗传途径。溶酶体相关细胞器（LRO）是一种特殊的膜结合细胞器，具有许多典型溶酶体的共同特征。LRO生物合成关键成分的突变导致人类免疫、血液凝固和色素沉着等疾病。在秀丽隐杆线虫中，LRO是与衰老相关的自发荧光和活体染料尼罗红的积累部位。优美的通过经典的遗传学，我们表明，LRO是由一个保守的遗传途径，涉及血清素，线粒体酮硫解酶，质子偶联溶质转运蛋白。虽然以前被认为是在一个强制性的方式连接，通过系统层次的分析，我们表明，积累的C。线虫LRO尼罗红和自发荧光是机制上不同的过程。与先前认为LRO尼罗红指示脂质储存的观点相反，我们表明LRO尼罗红与C. elegans脂质储存。使用数百个破坏尼罗红积累的候选基因失活，我们确定了哪些LRO调控基因与已知改变LRO生物学的6种遗传突变体特异性相互作用，确定了特异性依赖于雷帕霉素复合物2信号传导靶点的变化。这些数据揭示了LRO生物学与C.优雅的
Lysosomes are membrane-bound organelles that contain acid hydrolases that degrade cellular proteins, lipids, nucleic acids, and oligosaccharides, and are important for cellular maintenance and protection against age-related decline. Lysosome related organelles (LROs) are specialized lysosomes found in organisms from humans to worms, and share many of the features of classic lysosomes. Defective LROs are associated with human immune disorders and neurological disease. Caenorhabditis elegans LROs are the site of concentration of vital dyes such as Nile red as well as age-associated autofluorescence. Even though certain short-lived mutants have high LRO Nile red and high autofluorescence, and other long-lived mutants have low LRO Nile red and low autofluorescence, these two biologies are distinct. We identified a genetic pathway that modulates aging-related LRO phenotypes via serotonin signaling and the gene kat-1, which encodes a mitochondrial ketothiolase. Regulation of LRO phenotypes by serotonin and kat-1 in turn depend on the proton-coupled, transmembrane transporter SKAT-1. skat-1 loss of function mutations strongly suppress the high LRO Nile red accumulation phenotype of kat-1 mutation. Using a systems approach, we further analyzed the role of 571 genes in LRO biology. These results highlight a gene network that modulates LRO biology in a manner dependent upon the conserved protein kinase TOR complex 2. The results implicate new genetic pathways involved in LRO biology, aging related physiology, and potentially human diseases of the LRO. Lysosome related organelles (LROs) are specialized, membrane-bound organelles that share many common features of canonical lysosomes. Mutations in critical components of LRO biogenesis lead to human diseases of immunity, blood clotting, and pigmentation. In Caenorhabditis elegans, LROs are the site of accumulation of aging-related autofluorescence and the vital dye Nile red when fed to living C. elegans. Through classical genetics we show that the LRO is regulated by a conserved genetic pathway involving serotonin, a mitochondrial ketothiolase, and a proton-coupled solute transporter. Though previously thought to be linked in an obligatory manner, through systems level analysis we show that accumulation of C. elegans LRO Nile red and autofluorescence are mechanistically distinct processes. Contrary to the prior notion that LRO Nile red indicates lipid stores, we show that LRO Nile red is not correlated with, and may be anticorrelated with, C. elegans lipid stores. Using hundreds of candidate gene inactivations that disrupt Nile red accumulation, we determined which LRO regulatory genes specifically interact with 6 genetic mutants known to have altered LRO biology, identifying changes specifically dependent upon target of rapamycin complex 2 signaling. These data reveal relationships between LRO biology and aging and metabolism in C. elegans.
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影响因子：
3.7
作者：
Brooks KK;Liang B;Watts JL
通讯作者：
Watts JL
影响因子：
9.8
作者：
Coburn C;Allman E;Mahanti P;Benedetto A;Cabreiro F;Pincus Z;Matthijssens F;Araiz C;Mandel A;Vlachos M;Edwards SA;Fischer G;Davidson A;Pryor RE;Stevens A;Slack FJ;Tavernarakis N;Braeckman BP;Schroeder FC;Nehrke K;Gems D
通讯作者：
Gems D
影响因子：
3.3
作者：
Hermann, GJ;Schroeder, LK;Priess, JR
通讯作者：
Priess, JR
影响因子：
56.9
作者：
HORVITZ, HR;CHALFIE, M;EVANS, PD
通讯作者：
EVANS, PD
影响因子：
29
作者：
Mullaney BC;Blind RD;Lemieux GA;Perez CL;Elle IC;Faergeman NJ;Van Gilst MR;Ingraham HA;Ashrafi K
通讯作者：
Ashrafi K