Identification of Drosophila Yin and PEPT2 as Evolutionarily Conserved Phagosome-associated Muramyl Dipeptide Transporters
Identification of Drosophila Yin and PEPT2 as Evolutionarily Conserved Phagosome-associated Muramyl Dipeptide Transporters
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DOI：
10.1074/jbc.m110.115584
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发表时间：
2010-06-25
影响因子：
4.8
通讯作者：
Stuart, Lynda M.
中科院分区：
文献类型：
--
作者：
Charriere, Guillaume M.;Ip, W. K. Eddie;Stuart, Lynda M.
NOD2（核苷酸结合寡聚域2）是一种重要的细胞质模式识别受体，可激活nf - κ B和其他免疫效应途径，如自噬和抗原递呈。尽管NOD2定位于细胞内，但它也参与细胞外微生物的感知，如金黄色葡萄球菌。NOD2配体类似于最小合成配体muramyl dipeptide (MDP)，是由细菌在水解吞噬溶酶体中内化加工而产生的。然而，这些衍生的配体是如何离开细胞器并进入细胞质以激活NOD2的尚不清楚。在这里，我们讨论了吞噬体衍生的NOD2配体如何进入人类吞噬细胞的细胞质。根据果蝇吞噬体的数据，我们发现SLC15A转运体果蝇Yin和PEPT2分别在果蝇和人类吞噬细胞中作为MDP转运体发挥着进化上保守的作用。我们发现PEPT2在人髓细胞中高度表达。阴离子和PEPT2的异位表达增加了nod2依赖性nf - κ B激活的敏感性。此外，我们发现PEPT2与吞噬体膜相关。总之，这些数据确定了果蝇Yin和PEPT2是进化上保守的吞噬体相关转运体，它们可能在将吞噬体中产生的细菌衍生的配体运送到这些细胞器附近的细胞质传感器中特别重要。
NOD2 (nucleotide-binding oligomerization domain containing 2) is an important cytosolic pattern recognition receptor that activates NF-kappa B and other immune effector pathways such as autophagy and antigen presentation. Despite its intracellular localization, NOD2 participates in sensing of extracellular microbes such as Staphylococcus aureus. NOD2 ligands similar to the minimal synthetic ligand muramyl dipeptide (MDP) are generated by internalization and processing of bacteria in hydrolytic phagolysosomes. However, how these derived ligands exit this organelle and access the cytosol to activate NOD2 is poorly understood. Here, we address how phagosome-derived NOD2 ligands access the cytosol in human phagocytes. Drawing on data from Drosophila phagosomes, we identify an evolutionarily conserved role of SLC15A transporters, Drosophila Yin and PEPT2, as MDP transporters in fly and human phagocytes, respectively. We show that PEPT2 is highly expressed by human myeloid cells. Ectopic expression of both Yin and PEPT2 increases the sensitivity of NOD2-dependent NF-kappa B activation. Additionally, we show that PEPT2 associates with phagosome membranes. Together, these data identify Drosophila Yin and PEPT2 as evolutionarily conserved phagosome-associated transporters that are likely to be of particular importance in delivery of bacteria-derived ligands generated in phagosomes to cytosolic sensors recruited to the vicinity of these organelles.