Arginine Methylation of FOXO Transcription Factors Inhibits Their Phosphorylation by Akt
Arginine Methylation of FOXO Transcription Factors Inhibits Their Phosphorylation by Akt
复制标题
DOI：
10.1016/j.molcel.2008.09.013
复制
发表时间：
2008-10-24
期刊：
影响因子：
16
通讯作者：
Fukamizu, Akiyoshi
中科院分区：
文献类型：
--
作者：
Yamagata, Kazuyuki;Daitoku, Hiroaki;Fukamizu, Akiyoshi
叉头盒0（FOXO）转录因子是细胞存活的关键调节因子，通过PI 3 K-Akt信号通路负调控。Akt对FOXO的磷酸化导致细胞质定位，随后通过泛素-蛋白酶体系统降解。在这里，我们展示了FOXO 1调节蛋白质精氨酸甲基转移酶PRMT 1的范例。PRMT 1在Akt磷酸化的保守基序内的Arg 248和Arg 250处甲基化FOXO 1;这种甲基化在体外和体内直接阻断Akt介导的FOXO 1在Ser 253处的磷酸化。通过小干扰RNA沉默PRMT 1增强FOXO 1的核排斥、多聚泛素化和蛋白酶体降解。PRMT 1敲低导致氧化应激诱导的细胞凋亡减少，这取决于PI 3 K-Akt信号通路。此外，酶失活的PRMT 1突变体的稳定表达增加了对细胞凋亡的抗性，而这种作用被磷酸化缺陷FOXO 1的表达逆转。我们的研究结果预测了精氨酸甲基化作为对Akt介导的磷酸化的抑制性修饰的作用。
Forkhead box O (FOXO) transcription factors, the key regulators of cell survival, are negatively controlled through the PI3K-Akt signaling pathway. Phosphorylation of FOXO by Akt leads to cytoplasmic localization and subsequent degradation via the ubiquitin-proteasome system. Here we show a paradigm of FOXO1 regulation by the protein arginine methyltransferase PRMT1. PRMT1 methylated FOXO1 at conserved Arg248 and Arg250 within a consensus motif for Akt phosphorylation; this methylation directly blocked Akt-mediated phosphorylation of FOXO1 at Ser253 in vitro and in vivo. Silencing of PRMT1 by small interfering RNA enhanced nuclear exclusion, polyubiquitination, and proteasomal degradation of FOXO1. PRMT1 knockdown led to a decrease in oxidative-stress-induced apoptosis depending on the PI3K-Akt signaling pathway. Furthermore, stable expression of enzymatic inactive PRMT1 mutant increased resistance to apoptosis whereas this effect was reversed by expression of phosphorylation-deficient FOXO1. Our findings predict a role for arginine methylation as an inhibitory modification against Akt-mediated phosphorylation.