Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9

Ernest Y. Lee, Changsheng Zhang, Jeremy Di Domizio, Fan Jin, Will Connell, Mandy Hung, Nicolas Malkoff, Veronica Veksler, Michel Gilliet, Pengyu Ren () and Gerard C. L. Wong ()
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Ernest Y. Lee: University of California, Los Angeles
Changsheng Zhang: The University of Texas at Austin
Jeremy Di Domizio: Lausanne University Hospital CHUV
Fan Jin: University of Science and Technology of China
Will Connell: University of California, Los Angeles
Mandy Hung: University of California, Los Angeles
Nicolas Malkoff: University of California, Los Angeles
Veronica Veksler: University of California, Los Angeles
Michel Gilliet: Lausanne University Hospital CHUV
Pengyu Ren: The University of Texas at Austin
Gerard C. L. Wong: University of California, Los Angeles

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract Amphiphilicity in ɑ-helical antimicrobial peptides (AMPs) is recognized as a signature of potential membrane activity. Some AMPs are also strongly immunomodulatory: LL37-DNA complexes potently amplify Toll-like receptor 9 (TLR9) activation in immune cells and exacerbate autoimmune diseases. The rules governing this proinflammatory activity of AMPs are unknown. Here we examine the supramolecular structures formed between DNA and three prototypical AMPs using small angle X-ray scattering and molecular modeling. We correlate these structures to their ability to activate TLR9 and show that a key criterion is the AMP’s ability to assemble into superhelical protofibril scaffolds. These structures enforce spatially-periodic DNA organization in nanocrystalline immunocomplexes that trigger strong recognition by TLR9, which is conventionally known to bind single DNA ligands. We demonstrate that we can “knock in” this ability for TLR9 amplification in membrane-active AMP mutants, which suggests the existence of tradeoffs between membrane permeating activity and immunomodulatory activity in AMP sequences.

Date: 2019
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DOI: 10.1038/s41467-019-08868-w

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