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Recognition of bacterial signal peptides by mammalian formyl peptide receptors: a
new mechanism for sensing pathogens
#MMPMID25605714
Bufe B
; Schumann T
; Kappl R
; Bogeski I
; Kummerow C
; Podgórska M
; Smola S
; Hoth M
; Zufall F
J Biol Chem
2015[Mar]; 290
(12
): 7369-87
PMID25605714
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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.
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