Cell Signalling in Yeast Unit, Department of Basic Medical Sciences, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain.
Int J Mol Sci. 2023 Jan 26;24(3):2438. doi: 10.3390/ijms24032438.
Iron scarcity provokes a cellular response consisting of the strong expression of high-affinity systems to optimize iron uptake and mobilization. Aft1 is a primary transcription factor involved in iron homeostasis and controls the expression of high-affinity iron uptake genes in . Aft1 responds to iron deprivation by translocating from the cytoplasm to the nucleus. Here, we demonstrate that the AGC kinase Ypk1, as well as its upstream regulator TOR Complex 2 (TORC2), are required for proper Aft1 nuclear localization following iron deprivation. We exclude a role for TOR Complex 1 (TORC1) and its downstream effector Sch9, suggesting this response is specific for the TORC2 arm of the TOR pathway. Remarkably, we demonstrate that Aft1 nuclear localization and a robust transcriptional response to iron starvation also require biosynthesis of sphingolipids, including complex sphingolipids such as inositol phosphorylceramide (IPC) and upstream precursors, e.g., long-chain bases (LCBs) and ceramides. Furthermore, we observe the deficiency of Aft1 nuclear localization and impaired transcriptional response in the absence of iron when TORC2-Ypk1 is impaired is partially suppressed by exogenous addition of the LCB dihydrosphingosine (DHS). This latter result is consistent with prior studies linking sphingolipid biosynthesis to TORC2-Ypk1 signaling. Taken together, these results reveal a novel role for sphingolipids, controlled by TORC2-Ypk1, for proper localization and activity of Aft1 in response to iron scarcity.
缺铁会引发细胞反应，包括强烈表达高亲和力系统以优化铁的摄取和动员。Aft1 是一种参与铁稳态的主要转录因子，它控制着. 中高亲和力铁摄取基因的表达。Aft1 通过从细胞质易位到细胞核来响应缺铁。在这里，我们证明 AGC 激酶 Ypk1 及其上游调节物 TOR 复合物 2（TORC2）在缺铁后适当的 Aft1 核定位中是必需的。我们排除了 TOR 复合物 1（TORC1）及其下游效应物 Sch9 的作用，表明这种反应是 TOR 途径的 TORC2 臂特有的。值得注意的是，我们证明 Aft1 的核定位和对铁饥饿的强烈转录反应也需要鞘脂的生物合成，包括复杂鞘脂，如肌醇磷酸神经酰胺（IPC）和上游前体，例如长链碱基（LCB）和神经酰胺。此外，当 TORC2-Ypk1 受损时，我们观察到在缺铁时 Aft1 核定位和转录反应的缺陷，在外源添加 LCB 二氢神经酰胺（DHS）时部分得到抑制。后一结果与先前的研究一致，即鞘脂生物合成与 TORC2-Ypk1 信号通路有关。总之，这些结果揭示了鞘脂在 TORC2-Ypk1 控制下对 Aft1 适当定位和活性的新作用，以响应缺铁。
