NOD2 (nucleotide-binding oligomerization domain containing 2) is an important cytosolic pattern recognition receptor that activates NF-kappaB 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-kappaB 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.

The sera of human immunodeficiency virus type 1 (HIV-1)-infected subjects were examined for the presence of infectious HIV-1-antibody complexes by their ability to infect Fc gamma receptor (Fc gamma R)-bearing cells. Infection of Fc gamma R-bearing cells by a serum in which half of the p24 antigen was present in a form of immune complexes was inhibited by aggregated human immunoglobulin. Then in studies on 22 sera, 9 sera produced p24 antigen during 14 days of culture in U937 cells. HIV-1 p24 production was inhibited or delayed by the pretreatment of cells with aggregated human immunoglobulin in 6 of the 9 sera that were infectious. These results may reflect interactions between virus-antibody complexes and Fc gamma R-bearing cells in vivo because serum itself was used as the source of virus and virus-antibody complexes. The results indicate that infectious HIV-1 immune complexes are present in the circulation of HIV-1-infected patients.