Phosphorylation of Lysophosphatidylcholine Acyltransferase 2 at Ser34 Enhances Platelet-activating Factor Production in Endotoxin-stimulated Macrophages |
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Authors: | Ryo Morimoto Hideo Shindou Yoshiya Oda Takao Shimizu |
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Affiliation: | From the Departments of ‡Biochemistry and Molecular Biology and ;§Metabolome, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Tokyo 113-0033 and ;¶CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-8613, Japan |
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Abstract: | Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator that elicits various cellular functions under physiological and pathological conditions. We have recently identified two enzymes involved in PAF production: lysophosphatidylcholine acyltransferase-1 (LPCAT1) and LPCAT2. We found that LPCAT2 is highly expressed in inflammatory cells and is activated by lipopolysaccharide (LPS) treatment through Toll-like receptor 4. However, the molecular mechanism for the activation remains elusive. In this study, Phos-tag SDS-PAGE revealed the LPS-induced phosphorylation of LPCAT2. Furthermore, mass spectrometry and mutagenesis analyses identified Ser34 of LPCAT2 as the phosphorylation site to enhance the catalytic activities. The experiments using inhibitors and siRNA against MAPK cascades demonstrated that LPCAT2 phosphorylation through LPS-TLR4 signaling may directly depend on MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2). These findings develop a further understanding of both PAF production and phospholipid remodeling triggered by inflammatory stimuli. Specific inhibition of the PAF biosynthetic activity by phosphorylated LPCAT2 will provide a novel target for the regulation of inflammatory disorders. |
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Keywords: | Inflammation Innate Immunity Phosphatidylcholine Phospholipid Phospholipid Turnover MK2 Acyltransferase Lyso-PAF Acetyltransferase Phosphorylation |
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