PIMT is a novel and potent suppressor of endothelial activation.
PIMT is a novel and potent suppressor of endothelial activation.
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作者：
Zhang C;Guo ZF;Liu W;Kazama K;Hu L;Sun X;Wang L;Lee H;Lu L;Yang XF;Summer R;Sun J
促炎激动剂引起内皮细胞表面粘附分子的表达，以促进白细胞浸润到组织中。严格控制这一过程对于防止不必要的炎症和器官损伤非常重要。蛋白质L-异天冬氨酰O-甲基转移酶（PIMT）在经历应激诱导的蛋白质损伤的细胞中将异天冬氨酰残基转化为常规的甲基化形式。本研究的目的是确定PIMT在血管稳态中的作用。PIMT在小鼠肺内皮中大量表达，并且小鼠中的PIMT缺乏加剧了肺部炎症和LPS（脂多糖）的血管渗漏。此外，我们发现PIMT通过与TNF受体相关因子6（TRAF 6）的相互作用及其使卷曲螺旋结构域中的天冬酰胺残基甲基化的能力来抑制LPS诱导的Toll样受体信号传导。发现这种相互作用抑制TRAF 6寡聚化和自泛素化，从而阻止NF-κB反式激活和随后的内皮粘附分子表达。另外，PIMT还通过抑制ICAM-1的N-糖基化来抑制ICAM-1的表达，对蛋白质稳定性产生影响，最终转化为减少EC（内皮细胞）-白细胞相互作用。我们的研究已经确定PIMT作为一种新的和有效的抑制内皮细胞活化。总之，这些发现表明，PIMT的治疗靶向可能有效地限制炎症性血管疾病中的器官损伤。
Proinflammatory agonists provoke the expression of cell surface adhesion molecules on endothelium in order to facilitate leukocyte infiltration into tissues. Rigorous control over this process is important to prevent unwanted inflammation and organ damage. Protein L-isoaspartyl O-methyltransferase (PIMT) converts isoaspartyl residues to conventional methylated forms in cells undergoing stress-induced protein damage. The purpose of this study was to determine the role of PIMT in vascular homeostasis. PIMT is abundantly expressed in mouse lung endothelium and PIMT deficiency in mice exacerbated pulmonary inflammation and vascular leakage to LPS(lipopolysaccharide). Furthermore, we found that PIMT inhibited LPS-induced toll-like receptor signaling through its interaction with TNF receptor-associated factor 6 (TRAF6) and its ability to methylate asparagine residues in the coiled-coil domain. This interaction was found to inhibit TRAF6 oligomerization and autoubiquitination, which prevented NF-κB transactivation and subsequent expression of endothelial adhesion molecules. Separately, PIMT also suppressed ICAM-1 expression by inhibiting its N-glycosylation, causing effects on protein stability that ultimately translated into reduced EC(endothelial cell)-leukocyte interactions. Our study has identified PIMT as a novel and potent suppressor of endothelial activation. Taken together, these findings suggest that therapeutic targeting of PIMT may be effective in limiting organ injury in inflammatory vascular diseases.
亲环蛋白 J 通过阻断泛素链传感来限制炎症
影响因子：
16.6
作者：
Sheng C;Yao C;Wang Z;Chen H;Zhao Y;Xu D;Huang H;Huang W;Chen S
通讯作者：
Chen S