TY - JOUR
T1 - Signal inhibitory receptor on leukocytes-1 recognizes bacterial and endogenous amphipathic alpha-helical peptides
AU - Rumpret, Matevž
AU - von Richthofen, Helen J.
AU - van der Linden, Maarten
AU - Westerlaken, Geertje H.A.
AU - Talavera Ormeño, Cami
AU - van Strijp, Jos A.G.
AU - Landau, Meytal
AU - Ovaa, Huib
AU - van Sorge, Nina M.
AU - Meyaard, Linde
N1 - Funding Information:
We want to thank Bas Surewaard for providing the following plasmids: pTXΔ16, pTXΔ16–PSMα, pTXΔ16–PSMβ, and pTXΔ16–. This work was supported by a Vici grant from the Netherlands Organization for Scientific Research awarded to LM (NWO, grant no. 91815608). hld
Publisher Copyright:
© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
PY - 2021/10
Y1 - 2021/10
N2 - Signal inhibitory receptor on leukocytes-1 (SIRL-1) is a negative regulator of myeloid cell function and dampens antimicrobial responses. We here show that different species of the genus Staphylococcus secrete SIRL-1-engaging factors. By screening a library of single-gene transposon mutants in Staphylococcus aureus, we identified these factors as phenol-soluble modulins (PSMs). PSMs are amphipathic α-helical peptides involved in multiple aspects of staphylococcal virulence and physiology. They are cytotoxic and activate the chemotactic formyl peptide receptor 2 (FPR2) on immune cells. Human cathelicidin LL-37 is also an amphipathic α-helical peptide with antimicrobial and chemotactic activities, structurally and functionally similar to α-type PSMs. We demonstrate that α-type PSMs from multiple staphylococcal species as well as human cathelicidin LL-37 activate SIRL-1, suggesting that SIRL-1 recognizes α-helical peptides with an amphipathic arrangement of hydrophobicity, although we were not able to show direct binding to SIRL-1. Upon rational peptide design, we identified artificial peptides in which the capacity to ligate SIRL-1 is segregated from cytotoxic and FPR2-activating properties, allowing specific engagement of SIRL-1. In conclusion, we propose staphylococcal PSMs and human LL-37 as a potential new class of natural ligands for SIRL-1.
AB - Signal inhibitory receptor on leukocytes-1 (SIRL-1) is a negative regulator of myeloid cell function and dampens antimicrobial responses. We here show that different species of the genus Staphylococcus secrete SIRL-1-engaging factors. By screening a library of single-gene transposon mutants in Staphylococcus aureus, we identified these factors as phenol-soluble modulins (PSMs). PSMs are amphipathic α-helical peptides involved in multiple aspects of staphylococcal virulence and physiology. They are cytotoxic and activate the chemotactic formyl peptide receptor 2 (FPR2) on immune cells. Human cathelicidin LL-37 is also an amphipathic α-helical peptide with antimicrobial and chemotactic activities, structurally and functionally similar to α-type PSMs. We demonstrate that α-type PSMs from multiple staphylococcal species as well as human cathelicidin LL-37 activate SIRL-1, suggesting that SIRL-1 recognizes α-helical peptides with an amphipathic arrangement of hydrophobicity, although we were not able to show direct binding to SIRL-1. Upon rational peptide design, we identified artificial peptides in which the capacity to ligate SIRL-1 is segregated from cytotoxic and FPR2-activating properties, allowing specific engagement of SIRL-1. In conclusion, we propose staphylococcal PSMs and human LL-37 as a potential new class of natural ligands for SIRL-1.
KW - cathelicidin LL-37
KW - phenol-soluble modulin
KW - SIRL-1
KW - Staphylococcus
UR - https://www.scopus.com/pages/publications/85115849087
U2 - 10.1096/fj.202100812R
DO - 10.1096/fj.202100812R
M3 - Article
AN - SCOPUS:85115849087
SN - 0892-6638
VL - 35
SP - 1
EP - 19
JO - FASEB Journal
JF - FASEB Journal
IS - 10
M1 - e21875
ER -