NSun2 Deficiency Protects Endothelium From Inflammation via mRNA Methylation of ICAM-1
Rationale: Vascular endothelial inflammation, including the expression of intercellular adhesion molecule 1 (ICAM-1), is a key event in vascular diseases. However, the mechanisms underlying the regulation of ICAM-1 are largely unknown.
Objective: To investigate the mechanisms on the regulation of ICAM-1 by NSun2-mediated mRNA methylation and the impact of NSun2-ICAM-1 regulatory process in vascular inflammation and allograft arteriosclerosis.
Methods and Results: By using in vitro, in cells and in vivo methylation assays, we showed that the tRNA methyltransferase NSun2 methylated the ICAM-1 mRNA. Methylation by NSun2 promoted the translation of ICAM-1, thereby increasing the adhesion of leukocytes to endothelial cells. TNFα or homocysteine (Hcy) activated the methyltransferase activity of NSun2 by repressing the phosphorylation of NSun2 by Aurora-B. The levels of ICAM-1 induction and of leukocyte adhesion to vascular endothelium observed with Hcy treatment in wild type rats were markedly decreased in NSun2 -/- rats. In a rat model of aortic allograft, the lack of donor NSun2 impaired the formation of allograft arteriosclerosis.
Conclusions: NSun2 upregulates the expression of ICAM-1 by methylating ICAM-1 mRNA. This regulatory process impacts on vascular inflammation and allograft arteriosclerosis.
- mRNA methylation
- vascular inflammation
- intercellular adhesion molecule-1
- Received September 23, 2015.
- Revision received January 27, 2016.
- Accepted January 29, 2016.