Teixeira Vitor, Medeiros Tânia C, Vilaça Rita, Moradas-Ferreira Pedro, Costa Vítor
Instituto de Biologia Molecular e Celular, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal. ; Departamento de Biologia Molecular, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Instituto de Biologia Molecular e Celular, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.
Microb Cell. 2014 Jan 6;1(1):21-36. doi: 10.15698/mic2014.01.121.
The target of rapamycin (TOR) is an important signaling pathway on a hierarchical network of interacting pathways regulating central biological processes, such as cell growth, stress response and aging. Several lines of evidence suggest a functional link between TOR signaling and sphingolipid metabolism. Here, we report that the TORC1-Sch9p pathway is activated in cells lacking Isc1p, the yeast orthologue of mammalian neutral sphingomyelinase 2. The deletion of or abolishes the premature aging, oxidative stress sensitivity and mitochondrial dysfunctions displayed by Δ cells and this is correlated with the suppression of the autophagic flux defect exhibited by the mutant strain. The protective effect of deletion, as opposed to that of deletion, is not associated with the attenuation of Hog1p hyperphosphorylation, which was previously implicated in Δ phenotypes. Our data support a model in which Isc1p regulates mitochondrial function and chronological lifespan in yeast through the TORC1-Sch9p pathway although Isc1p and TORC1 also seem to act through independent pathways, as ΔΔ phenotypes are intermediate to those displayed by Δ and Δ cells. We also provide evidence that TORC1 downstream effectors, the type 2A protein phosphatase Sit4p and the AGC protein kinase Sch9p, integrate nutrient and stress signals from TORC1 with ceramide signaling derived from Isc1p to regulate mitochondrial function and lifespan in yeast. Overall, our results show that TORC1-Sch9p axis is deregulated in Isc1p-deficient cells, contributing to mitochondrial dysfunction, enhanced oxidative stress sensitivity and premature aging of Δ cells.
雷帕霉素靶蛋白（TOR）是相互作用通路的层次网络中的一条重要信号通路，该网络调节着诸如细胞生长、应激反应和衰老等核心生物学过程。多条证据表明TOR信号传导与鞘脂代谢之间存在功能联系。在此，我们报告在缺乏Isc1p（哺乳动物中性鞘磷脂酶2的酵母同源物）的细胞中，TORC1-Sch9p通路被激活。删除 或 可消除Δ细胞所表现出的早衰、氧化应激敏感性和线粒体功能障碍，这与突变菌株自噬通量缺陷的抑制相关。与删除 相反，删除 的保护作用与Hog1p过度磷酸化的减弱无关，Hog1p过度磷酸化先前被认为与Δ表型有关。我们的数据支持一种模型，即Isc1p通过TORC1-Sch9p通路调节酵母中的线粒体功能和时序寿命，尽管Isc1p和TORC1似乎也通过独立的通路起作用，因为ΔΔ表型介于Δ和Δ细胞所表现出的表型之间。我们还提供证据表明，TORC1的下游效应器，即2A型蛋白磷酸酶Sit4p和AGC蛋白激酶Sch9p，将来自TORC1的营养和应激信号与源自Isc1p的神经酰胺信号整合起来，以调节酵母中的线粒体功能和寿命。总体而言，我们的结果表明，在缺乏Isc1p的细胞中，TORC1-Sch9p轴失调，导致Δ细胞的线粒体功能障碍、氧化应激敏感性增强和早衰。
