School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Cell Death Differ. 2012 May;19(5):859-70. doi: 10.1038/cdd.2011.168. Epub 2011 Nov 18.
Protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is implicated in modulation of cellular processes including gene transcription. The role of PRMTs in the regulation of intracellular signaling pathways has remained obscure, however. We now show that PRMT1 methylates apoptosis signal-regulating kinase 1 (ASK1) at arginine residues 78 and 80 and thereby negatively regulates ASK1 signaling. PRMT1-mediated ASK1 methylation attenuated the H(2)O(2)-induced stimulation of ASK1, with this inhibitory effect of PRMT1 being abolished by replacement of arginines 78 and 80 of ASK1 with lysine. Furthermore, depletion of PRMT1 expression by RNA interference potentiated H(2)O(2)-induced stimulation of ASK1. PRMT1-mediated ASK1 methylation promoted the interaction between ASK1 and its negative regulator thioredoxin, whereas it abrogated the association of ASK1 with its positive regulator TRAF2. Moreover, PRMT1 depletion potentiated paclitaxel-induced ASK1 activation and apoptosis in human breast cancer cells. Together, our results indicate that arginine methylation of ASK1 by PRMT1 contributes to the regulation of stress-induced signaling that controls a variety of cellular events including apoptosis.
蛋白质精氨酸甲基化，由蛋白质精氨酸甲基转移酶（PRMTs）催化，参与细胞过程的调节，包括基因转录。然而，PRMTs 在细胞内信号通路调节中的作用仍然不清楚。我们现在表明，PRMT1 甲基化凋亡信号调节激酶 1（ASK1）在精氨酸残基 78 和 80 上，从而负调控 ASK1 信号。PRMT1 介导的 ASK1 甲基化减弱了 H2O2 诱导的 ASK1 刺激，这种 PRMT1 的抑制作用被 ASK1 的精氨酸 78 和 80 替换为赖氨酸所消除。此外，RNA 干扰使 PRMT1 表达缺失增强了 H2O2 诱导的 ASK1 刺激。PRMT1 介导的 ASK1 甲基化促进了 ASK1 与其负调节剂硫氧还蛋白之间的相互作用，而消除了 ASK1 与其正调节剂 TRAF2 的结合。此外，PRMT1 缺失增强了紫杉醇诱导的人乳腺癌细胞中 ASK1 的激活和凋亡。总之，我们的结果表明，PRMT1 对 ASK1 的精氨酸甲基化有助于调节应激诱导的信号，控制包括凋亡在内的各种细胞事件。
