Histone H3K4 methyltransferase Mll1 regulates protein glycosylation and tunicamycin-induced apoptosis through transcriptional regulation
Histone H3K4 methyltransferase Mll1 regulates protein glycosylation and tunicamycin-induced apoptosis through transcriptional regulation
复制标题
组蛋白H3K4甲基转移酶Mll1通过转录调控调节蛋白质糖基化和衣霉素诱导的细胞凋亡
DOI：
10.1016/j.bbamcr.2014.06.013
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发表时间：
2014-11-01
影响因子：
5.1
通讯作者：
Li, Lianyun
中科院分区：
文献类型：
--
作者：
Wang, Xiang;Ju, Lingao;Li, Lianyun
破坏蛋白质糖基化诱导ER（内质网）应激，导致UPR（未折叠蛋白反应）途径的激活。UPR的一个关键功能是恢复ER稳态，但长期或未解决的ER应激可导致细胞凋亡。MLL 1（Mixed Lineage Leukemia 1，又称ALL-1或HEX）是哺乳动物中的一种组蛋白H3 K4甲基转移酶，在白血病的发生、转录调控、细胞周期和发育中起重要作用。在这里，我们发现，MIII缺乏增强UPR和诱导的糖基化抑制剂TM（衣霉素）的细胞凋亡。UPR的异常调节似乎是由蛋白质糖基化缺陷引起的。此外，Mll 1直接结合H6 pd、Galnt 12和Ugp 2的启动子，其调节H3 K4三甲基化和随后这些基因的表达。H6 pd、Galnt 12或Ugp 2的敲低增强了TM诱导的Mll 1（+/+）MEF细胞凋亡，而这些蛋白的异位表达抑制了TM诱导的Mll 1（-/-）MEF细胞凋亡。总之，我们的数据表明，糖蛋白在ER的成熟是受调控的表观遗传水平的组蛋白甲基转移酶，其异常可能导致癌症和发育缺陷。(C)2014爱思唯尔有限公司版权所有。
Disrupting protein glycosylation induces ER (endoplasmic reticulum) stress, resulting in the activation of UPR (unfolded protein response) pathways. A key function of the UPR is to restore ER homeostasis, but prolonged or unsolved ER stress can lead to apoptosis. MLL1 (Mixed Lineage Leukemia 1, also named ALL-1 or HEX), a histone H3K4 methyltransferase in mammals, plays important roles in leukemogenesis, transcriptional regulation, cell cycle and development. Here, we find that MIII deficiency enhances UPR and apoptosis induced by the glycosylation inhibitor TM (tunicamycin). The abnormal regulation of the UPR appears to be caused by a defect in protein glycosylation. Furthermore, Mll1 directly binds to the promoters of H6pd, Galnt12 and Ugp2, which regulates H3K4 trimethylation and the subsequent expression of these genes. The knockdown of H6pd, Galnt12 or Ugp2 enhances TM-induced apoptosis in Mll1(+/+) MEF cells, whereas the ectopic expression of these proteins inhibits TM-induced apoptosis in Mll1(-/-) MEF cells. Together, our data suggest that the maturation of glycoproteins in the ER is subject to regulation at the epigenetic level by a histone methyltransferase whose abnormality can lead to cancer and developmental defects. (C) 2014 Elsevier B.V. All rights reserved.