Endosomes are specialized platforms for bacterial sensing and NOD2 signalling
Endosomes are specialized platforms for bacterial sensing and NOD2 signalling
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DOI：
10.1038/nature13133
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发表时间：
2014-05-08
期刊：
影响因子：
64.8
通讯作者：
Mellman, Ira
中科院分区：
文献类型：
--
作者：
Nakamura, Norihiro;Lill, Jennie R.;Mellman, Ira
微生物病原体的检测涉及通过宿主细胞传感器如Toll样受体（TLR）和NOD样受体（NLR）识别保守的微生物组分。TLR是膜受体，其调查微生物感染的细胞外环境，而NLR是细胞溶质复合物，其检测到达细胞溶质的微生物产物。在检测时，两种传感器类别都会触发先天性炎症反应，并允许参与适应性免疫（1，2）。内溶体是多种病原体的进入位点，因此是免疫系统首先感觉到它们存在的位点。众所周知，通过内吞作用内化的病原体激活TLR 3和7-9，TLR 3和7-9定位于内吞区室并检测存在于内体腔中的配体（3）。内化的病原体也激活胞质溶胶中的传感器，如NOD 1和NOD 2（参考文献2），表明内体也提供细菌组分穿过内体膜的易位。尽管NOD 2在调节先天性免疫应答中具有关键作用，并且NOD 2基因座的突变是炎症性肠病和可能的其他慢性炎症状态中的常见风险因素（4，5），但对其配体如何从内体逃逸知之甚少。在这里，我们表明，两个内溶酶体肽转运蛋白，SLC 15 A3和SLC 15 A4，优先表达的树突状细胞，特别是TLR刺激后。转运蛋白介导细菌衍生组分的流出，例如NOD 2同源配体胞壁酰二肽（MDP）（6，7），并且是NOD 2对内体衍生MDP的应答选择性所需的。增强的转运蛋白表达还产生树突状细胞的内体膜小管特征，这进一步增强了对MDP的NOD 2依赖性应答。最后，传感需要将NOD 2及其效应激酶RIPK 2（参考文献8，9）募集到内体膜，可能是通过与SLC 15 A3或SLC 15 A4形成复合物。因此，树突状细胞内体是用于病原体的内腔和胞质传感的专门平台。
The detection of microbial pathogens involves the recognition of conserved microbial components by host cell sensors such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). TLRs are membrane receptors that survey the extracellular environment for microbial infections, whereas NLRs are cytosolic complexes that detect microbial products that reach the cytosol. Upon detection, both sensor classes trigger innate inflammatory responses and allow the engagement of adaptive immunity(1,2). Endo-lysosomes are the entry sites for a variety of pathogens, and therefore the sites at which the immune system first senses their presence. Pathogens internalized by endocytosis are well known to activate TLRs 3 and 7-9 that are localized to endocytic compartments and detect ligands present in the endosomal lumen(3). Internalized pathogens also activate sensors in the cytosol such as NOD1 and NOD2 (ref. 2), indicating that endosomes also provide for the translocation of bacterial components across the endosomal membrane. Despite the fact that NOD2 is well understood to have a key role in regulating innate immune responses and that mutations at the NOD2 locus are a common risk factor in inflammatory bowel disease and possibly other chronic inflammatory states(4,5), little is known about how its ligands escape from endosomes. Here we show that two endo-lysosomal peptide transporters, SLC15A3 and SLC15A4, are preferentially expressed by dendritic cells, especially after TLR stimulation. The transporters mediate the egress of bacterially derived components, such as the NOD2 cognate ligand muramyl dipeptide (MDP)(6,7), and are selectively required for NOD2 responses to endosomally derived MDP. Enhanced expression of the transporters also generates endosomal membrane tubules characteristic of dendritic cells, which further enhanced the NOD2-dependent response to MDP. Finally, sensing required the recruitment of NOD2 and its effector kinase RIPK2 (refs 8, 9) to the endosomal membrane, possibly by forming a complex with SLC15A3 or SLC15A4. Thus, dendritic cell endosomes are specialized platforms for both the lumenal and cytosolic sensing of pathogens.