Adenylyl Cyclase 6 Activation Negatively Regulates TLR4 Signaling through Lipid Raft-Mediated Endocytosis
Adenylyl Cyclase 6 Activation Negatively Regulates TLR4 Signaling through Lipid Raft-Mediated Endocytosis
复制标题
腺苷酸环化酶 6 激活通过脂筏介导的内吞作用负调节 TLR4 信号传导
DOI：
10.4049/jimmunol.1301912
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发表时间：
2013-12-15
影响因子：
4.4
通讯作者：
Xu, Congfeng
中科院分区：
文献类型：
--
作者：
Cai, Wei;Du, Ailian;Xu, Congfeng
Proper intracellular localization of TLRs is essential for their signaling and biological function. Endocytosis constitutes a key step in protein turnover, as well as maintenance of TLR localization in plasma membrane and intracellular compartments, and thus provides important regulating points to their signaling. In this study, we demonstrate that adenylyl cyclase (AC) activation attenuates TLR4 signaling in a murine macrophage cell line (RAW 264.7) and bone marrow-derived macrophages when stimulated with LPS. We further show that the AC6 isoform plays a key role in negative regulation of TLR4 signaling by promoting protein degradation. TLR4 is normally endocytosed through the clathrin-mediated pathway, but concomitant AC6 activation shifts it to lipid raft-mediated endocytosis, which accelerates degradation of TLR4 and suppresses downstream signaling. Our studies unveil a new mechanism of negative regulation of TLR4 signaling through AC6-mediated endocytosis, which might provide a novel therapeutic approach for limiting inflammatory and autoimmune diseases.
