Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4

详细信息    查看全文

• 作者：Vincent A. van der Mark ; Mohammed Ghiboub…
• 关键词：P4 ; ATPase ; Phospholipid flippase ; ATP8B1 ; Endocytosis ; Innate immunity ; Macrophage
• 刊名：Cellular and Molecular Life Sciences
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：74
• 期：4
• 页码：715-730
• 全文大小：4309KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Cell Biology; Biomedicine, general; Life Sciences, general; Biochemistry, general;
• 出版者：Springer International Publishing
• ISSN：1420-9071
• 卷排序：74

文摘

P4-ATPases are lipid flippases that catalyze the transport of phospholipids to create membrane phospholipid asymmetry and to initiate the biogenesis of transport vesicles. Here we show, for the first time, that lipid flippases are essential to dampen the inflammatory response and to mediate the endotoxin-induced endocytic retrieval of Toll-like receptor 4 (TLR4) in human macrophages. Depletion of CDC50A, the β-subunit that is crucial for the activity of multiple P4-ATPases, resulted in endotoxin-induced hypersecretion of proinflammatory cytokines, enhanced MAP kinase signaling and constitutive NF-κB activation. In addition, CDC50A-depleted THP-1 macrophages displayed reduced tolerance to endotoxin. Moreover, endotoxin-induced internalization of TLR4 was strongly reduced and coincided with impaired endosomal MyD88-independent signaling. The phenotype of CDC50A-depleted cells was also induced by separate knockdown of two P4-ATPases, namely ATP8B1 and ATP11A. We conclude that lipid flippases are novel elements of the innate immune response that are essential to attenuate the inflammatory response, possibly by mediating endotoxin-induced internalization of TLR4.