Clathrin- and dynamin-dependent endocytic pathway regulates muramyl dipeptide internalization and NOD2 activation.
Clathrin- and dynamin-dependent endocytic pathway regulates muramyl dipeptide internalization and NOD2 activation.
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DOI：
10.4049/jimmunol.0802197
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发表时间：
2009-04-01
期刊：
影响因子：
--
通讯作者：
Núñez G
中科院分区：
文献类型：
--
作者：
Marina-García N;Franchi L;Kim YG;Hu Y;Smith DE;Boons GJ;Núñez G
胞壁酰二肽（MDP）是NOD 2激动剂，其诱导NF-κB和MAPK活化，导致产生抗微生物和促炎分子。MDP被内化到巨噬细胞中的酸化囊泡中。然而，诱导NOD 2信号转导的MDP摄取的内吞机制尚不清楚。我们现在报告的识别依赖于网格蛋白和发动蛋白介导的MDP内化和NOD 2激活的内吞途径。胞内MDP摄取被氯丙嗪抑制，氯丙嗪是一种破坏网格蛋白依赖性内吞作用的药物，但不被阻断胞饮作用或通过清道夫或甘露糖受体进入细胞的化合物抑制。相比之下，MDP摄取和NOD 2依赖性信号传导在巨噬细胞缺乏PepT 1中未受损，PepT 1是一种先前参与MDP内化的肽转运蛋白。氯丙嗪和通过RNA干扰敲低网格蛋白表达均减弱了MDP诱导的NF-κB和MAPK活化。此外，MDP摄取和NOD 2依赖性信号传导受损的抑制动力蛋白，GTdR需要从质膜的网格蛋白包被的囊泡出芽。最后，巴弗洛霉素A，一个特定的抑制剂的液泡质子泵，阻止MDP积累在酸化囊泡和细胞因子的反应，表明液泡成熟是重要的MDP诱导的NOD 2信号。这些研究为介导MDP摄取和NOD 2活化的网格蛋白和动力蛋白依赖性内吞途径提供了证据。
Muramyl dipeptide (MDP), the NOD2 agonist, induces NF-κB and MAPK activation leading to the production of anti-microbial and pro-inflammatory molecules. MDP is internalized into acidified vesicles in macrophages. However, the endocytic mechanism of MDP uptake that induces NOD2 signaling is unknown. We now report the identification of an endocytosis pathway dependent on clathrin and dynamin that mediates MDP internalization and NOD2 activation. Intracellular MDP uptake was inhibited by chlorpromazine, a drug that disrupts clathrin-dependent endocytosis, but not by compounds that block pinocytosis or cellular entry via scavenger or mannose receptors. In contrast, MDP uptake and NOD2-dependent signaling were unimpaired in macrophages deficiency in PepT1, a peptide transporter previously implicated in MDP internalization. Both chlorpromazine and knockdown of clathrin expression by RNA interference attenuated MDP-induced NF-κB and MAPK activation. Furthermore, MDP uptake and NOD2-dependent signaling were impaired by inhibition of dynamin, a GTPase required for budding of clathrin-coated vesicles from the plasma membrane. Finally, bafilomycin A, a specific inhibitor of the vacuolar proton pump, blocked MDP accumulation in acidified vesicles and cytokine responses, suggesting that vacuolar maturation is important for MDP-induced NOD2 signaling. These studies provide evidence for a clathrin- and dynamin-dependent endocytosis pathway that mediates MDP uptake and NOD2 activation.
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