Bacterial peptide recognition and immune activation facilitated by human peptide transporter PEPT2

Peter W. Swaan, Timothy Bensman, Praveen M. Bahadduri, Mark W. Hall, Anasuya Sarkar, Shengying Bao, Chandra M. Khantwal, Sean Ekins, Daren L. Knoell

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Microbial detection requires the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) that are distributed on the cell surface and within the cytosol. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family functions as an intracellular PRR that triggers the innate immune response. The mechanism by which PAMPs enter the cytosol to interact with NLRs, particularly muropeptides derived from the bacterial proteoglycan cell wall, is poorly understood. PEPT2 is a proton-dependent transporter that mediates the active translocation of di- and tripeptides across epithelial tissues, including the lung. Using computational tools, we initially established that bacterial dipeptides, particularly γ-D-glutamyl-meso-diaminopimelic acid (γ-iE-DAP), are suitable substrates for PEPT2. We then determined in primary cultures ofhumanupper airway epithelia and transiently transfected CHO-PEPT2 cell lines that γ-iE-DAP uptake was mediated by PEPT2 with an affinity constant of approximately 193 μM, whereas muramyl dipeptide was not transported. Exposure to γ-iE-DAP at the apical surface of differentiated, polarized cultures resulted in activation of the innate immune response in an NOD1- and RIP2-dependent manner, resulting in release of IL-6 and IL-8. Based on these findings we report that PEPT2 plays a vital role in microbial recognition by NLR proteins, particularly with regard to airborne pathogens, thereby participating in host defense in the lung.

Original languageEnglish (US)
Pages (from-to)536-542
Number of pages7
JournalAmerican journal of respiratory cell and molecular biology
Volume39
Issue number5
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

Keywords

  • Acute phase reactants
  • Bacterial
  • Cell surface molecules
  • Human
  • Lung

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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