Post-translational methylation of high mobility group box 1 (HMGB1) causes its cytoplasmic localization in neutrophils
Post-translational methylation of high mobility group box 1 (HMGB1) causes its cytoplasmic localization in neutrophils
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DOI：
10.1074/jbc.m608467200
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Yoshida, Michiteru
中科院分区：
文献类型：
--
作者：
Ito, Ichiaki;Fukazawa, Jutarou;Yoshida, Michiteru
高迁移率组框1蛋白（HMGB1）在转录、复制和细胞分化过程中发挥着多种作用。HMGB1也由活化的单核细胞和巨噬细胞分泌，并由坏死或受损细胞被动释放，刺激炎症。HMGB1是在溃疡性结肠炎和自身免疫性肝炎患者血清中发现的抗中性粒细胞胞浆抗体（ANCA）的一种新型抗原，提示HMGB1是由中性粒细胞分泌到细胞外环境的。然而，HMGB1在中性粒细胞细胞质中的实际分布及其机制尚不清楚。我们发现中性粒细胞中的HMGB1在Lys42位点发生翻译后单甲基化。甲基化改变了HMGB1的构象，削弱了其DNA结合活性，使其通过被动扩散到细胞核外，在细胞质中大量分布。因此，hmgb1的翻译后甲基化导致其在中性粒细胞中的胞质定位。这一新途径解释了核HMGB1向细胞质的分布，并对了解中性粒细胞如何将HMGB1释放到细胞外环境具有重要意义。
High mobility group box 1 (HMGB1) protein plays multiple roles in transcription, replication, and cellular differentiation. HMGB1 is also secreted by activated monocytes and macrophages and passively released by necrotic or damaged cells, stimulating inflammation. HMGB1 is a novel antigen of antineutrophil cytoplasmic antibodies (ANCA) observed in the sera of patients with ulcerative colitis and autoimmune hepatitis, suggesting that HMGB1 is secreted from neutrophils to the extracellular milieu. However, the actual distribution of HMGB1 in the cytoplasm of neutrophils and the mechanisms responsible for it are obscure. Here we show that HMGB1 in neutrophils is post- translationally mono-methylated at Lys42. The methylation alters the conformation of HMGB1 and weakens its DNA binding activity, causing it to become largely distributed in the cytoplasm by passive diffusion out of the nucleus. Thus, post- translational methylation ofHMGB1causes its cytoplasmic localization in neutrophils. This novel pathway explains the distribution of nuclear HMGB1 to the cytoplasm and is important for understanding how neutrophils release HMGB1 to the extracellular milieu.