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dc.contributor.authorCharriere, Guillaume M.
dc.contributor.authorIp, Wk Eddie
dc.contributor.authorDejardin, Stephanie
dc.contributor.authorBoyer, Laurent
dc.contributor.authorSokolovska, Anna
dc.contributor.authorCappillino, Michael P.
dc.contributor.authorCherayil, Bobby J.
dc.contributor.authorPodolsky, Daniel K.
dc.contributor.authorKobayashi, Koichi S.
dc.contributor.authorSilverman, Neal S.
dc.contributor.authorLacy-Hulbert, Adam
dc.contributor.authorStuart, Lynda M.
dc.date2022-08-11T08:09:10.000
dc.date.accessioned2022-08-23T16:20:03Z
dc.date.available2022-08-23T16:20:03Z
dc.date.issued2010-04-22
dc.date.submitted2010-10-01
dc.identifier.citationJ Biol Chem. 2010 Jun 25;285(26):20147-54. Epub 2010 Apr 20. <a href="http://dx.doi.org/10.1074/jbc.M110.115584">Link to article on publisher's site</a>
dc.identifier.issn0021-9258 (Linking)
dc.identifier.doi10.1074/jbc.M110.115584
dc.identifier.pmid20406817
dc.identifier.urihttp://hdl.handle.net/20.500.14038/35194
dc.description.abstractNOD2 (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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=20406817&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1074/jbc.M110.115584
dc.subjectAcetylmuramyl-Alanyl-Isoglutamine
dc.subjectAnimals
dc.subjectCell Line
dc.subjectDrosophila Proteins
dc.subjectEvolution, Molecular
dc.subjectGreen Fluorescent Proteins
dc.subjectHost-Pathogen Interactions
dc.subjectHumans
dc.subjectInterleukin-6
dc.subjectMacrophages
dc.subjectMembrane Transport Proteins
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectMicroscopy, Confocal
dc.subjectNF-kappa B
dc.subjectNod2 Signaling Adaptor Protein
dc.subjectPhagosomes
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectStaphylococcus aureus
dc.subjectSymporters
dc.subjectToll-Like Receptor 2
dc.subjectToll-Like Receptor 6
dc.subjectTransfection
dc.subjectTumor Necrosis Factor-alpha
dc.subjectImmunology and Infectious Disease
dc.titleIdentification of Drosophila Yin and PEPT2 as evolutionarily conserved phagosome-associated muramyl dipeptide transporters
dc.typeJournal Article
dc.source.journaltitleThe Journal of biological chemistry
dc.source.volume285
dc.source.issue26
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/infdis_pp/42
dc.identifier.contextkey1589374
html.description.abstract<p>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.</p>
dc.identifier.submissionpathinfdis_pp/42
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pages20147-54


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