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.
Highlights
The function of formyl peptide receptors (FPRs) is incompletely understood
We report the identification of bacterial signal peptides as potent activators of mammalian FPRs and innate immune responses and define critical features underlying FPR peptide recognition
Initial experiments revealed that two peptides exhibiting highly divergent chemical structures, MMHWAm (M-peptide) (35) and WKYMVm (W-peptide) (36) (Fig. 1A), that carry an amidated D-methionine at their C terminus and their stereoisomers with an amidated L-methionine caused surprisingly similar activation of mFpr-rs[1], one of the FPRs expressed in the mouse vomeronasal organ, with respect to concentration, stereoselective preference, and the relative potency of D- versus L-isoforms (Fig. 1, B–D)
Summary
The function of formyl peptide receptors (FPRs) is incompletely understood. Results: We report the identification of bacterial signal peptides as potent activators of mammalian FPRs and innate immune responses and define critical features underlying FPR peptide recognition. 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. Dynamic measurements in human and mouse innate immune cells demonstrate that all tested signal peptides are recognized by these cells and trigger classical innate immune responses, such as intracellular Ca2ϩ mobilization, generation of reactive oxygen species, release of metallopeptidase, and chemotactic cell migration These observations argue that mammalian FPRs may have evolved originally as germ line-encoded pattern recognition receptors that recognize structurally conserved export motifs of bacterial signal sequences as their cognate, pathogenassociated molecular pattern
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