title: Recognition of bacterial signal peptides by mammalian formyl peptide receptors: a new mechanism for sensing pathogens.
abstract: Formyl peptide receptors (FPRs) are G-protein-coupled receptors that function as chemoattractant receptors in innate immune responses. Here we perform systematic structure-function analyses of FPRs from six mammalian species using structurally diverse FPR peptide agonists and identify a common set of conserved agonist properties with typical features of pathogen-associated molecular patterns. Guided by these results, we discover that bacterial signal peptides, normally used to translocate proteins across cytoplasmic membranes, are a vast family of natural FPR agonists. N-terminally formylated signal peptide fragments with variable sequence and length activate human and mouse FPR1 and FPR2 at low nanomolar concentrations, thus establishing FPR1 and FPR2 as sensitive and broad signal peptide receptors. The vomeronasal receptor mFpr-rs1 and its sequence orthologue hFPR3 also react to signal peptides but are much more narrowly tuned in signal peptide recognition. Furthermore, all signal peptides examined here function as potent activators of the innate immune system. They elicit robust, FPR-dependent calcium mobilization in human and mouse leukocytes and trigger a range of classical innate defense mechanisms, such as the production of reactive oxygen species, metalloprotease release, and chemotaxis. Thus, bacterial signal peptides constitute a novel class of immune activators that are likely to contribute to mammalian immune defense against bacteria. This evolutionarily conserved detection mechanism combines structural promiscuity with high specificity and enables discrimination between bacterial and eukaryotic signal sequences. With at least 175,542 predicted sequences, bacterial signal peptides represent the largest and structurally most heterogeneous class of G-protein-coupled receptor agonists currently known for the innate immune system.
authors.affiliation: From the Departments of Physiology, bernd.bufe@uks.eu.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bufe
authors.affiliation: From the Departments of Physiology.
authors.forename: Timo
authors.initials: T
authors.lastname: Schumann
authors.affiliation: Biophysics, and.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kappl
authors.affiliation: Biophysics, and.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bogeski
authors.affiliation: Biophysics, and.
authors.forename: Carsten
authors.initials: C
authors.lastname: Kummerow
authors.affiliation: Virology, University of Saarland School of Medicine, 66421 Homburg, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Podgórska
authors.affiliation: Virology, University of Saarland School of Medicine, 66421 Homburg, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
authors.affiliation: Biophysics, and.
authors.forename: Markus
authors.initials: M
authors.lastname: Hoth
authors.affiliation: From the Departments of Physiology.
authors.forename: Frank
authors.initials: F
authors.lastname: Zufall
mesh_terms: D000595:Amino Acid Sequence; D001419:Bacteria / Q000302:isolation & purification*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D021382:Protein Sorting Signals; D044042:Receptors, Formyl Peptide / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D021382:Protein Sorting Signals; D044042:Receptors, Formyl Peptide
keywords: Calcium Imaging; Chemical Biology; G-protein-coupled Receptor (GPCR); Innate Immunity; Molecular Pharmacology; Pathogen-associated Molecular Pattern (PAMP); Pattern Recognition Receptor (PRR); Vomeronasal Organ (VNO)