Decreased MORF leads to prolonged endoplasmic reticulum stress in periodontitis-associated chronic inflammation
Decreased MORF leads to prolonged endoplasmic reticulum stress in periodontitis-associated chronic inflammation
复制标题
MORF 降低导致牙周炎相关慢性炎症中内质网应激延长
DOI：
10.1038/cdd.2016.74
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发表时间：
2016-11-01
影响因子：
12.4
通讯作者：
Jin, Yan
中科院分区：
文献类型：
--
作者：
Xue, Peng;Li, Bei;Jin, Yan
炎症与内质网 (ER) 应激之间的关联已在许多疾病中得到描述。然而，慢性炎症是否以及如何控制未折叠蛋白反应（UPR）并促进慢性炎症性疾病的内质网稳态仍然难以捉摸。在这项研究中，慢性炎症导致牙周炎背景下间充质干细胞内质网应激。长期促炎细胞因子诱导延长的内质网应激并降低牙周膜干细胞（PDLSC）的成骨分化。有趣的是，我们发现慢性炎症会降低赖氨酸乙酰转移酶 6B（KAT6B，也称为 MORF）（一种组蛋白乙酰转移酶）的表达，并导致关键 UPR 传感器 PERK 的上调，从而导致 PDLSC 中 UPR 的持续激活。此外，我们发现慢性炎症中 MORF 介导的 UPR 激活会导致体内和体外 PDLSC 成骨分化的 PERK 相关恶化。综上所述，我们的结果表明，慢性炎症通过 MORF 介导的 PERK 转录损害 UPR 功能，这是一种以前未被认识的机制，会导致牙周炎中 ER 功能受损、ER 应激延长和 PDLSC 成骨分化缺陷。
The association between inflammation and endoplasmic reticulum (ER) stress has been described in many diseases. However, if and how chronic inflammation governs the unfolded protein response (UPR) and promotes ER homeostasis of chronic inflammatory disease remains elusive. In this study, chronic inflammation resulted in ER stress in mesenchymal stem cells in the setting of periodontitis. Long-term proinflammatory cytokines induced prolonged ER stress and decreased the osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Interestingly, we showed that chronic inflammation decreases the expression of lysine acetyltransferase 6B (KAT6B, also called MORF), a histone acetyltransferase, and causes the upregulation of a key UPR sensor, PERK, which lead to the persistent activation of the UPR in PDLSCs. Furthermore, we found that the activation of UPR mediated by MORF in chronic inflammation contributes to the PERK-related deterioration of the osteogenic differentiation of PDLSCs both in vivo and in vitro. Taken together, our results suggest that chronic inflammation compromises UPR function through MORF-mediated-PERK transcription, which is a previously unrecognized mechanism that contributes to impaired ER function, prolonged ER stress and defective osteogenic differentiation of PDLSCs in periodontitis.