Journal Article

DZNE-2026-00774

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png RNA selectively modulates activity of virulent amyloid PSMα3 and host-defense LL-37 via phase separation and aggregation dynamics.

Rayan, B. ; Barnea, E. ; Indig, R. ; Pantoja, C. F.DZNE* ; Gayk, J. ; Lupu-Haber, Y. ; Upcher, A. ; Argoetti, A. ; Larsen, J. A. ; Buell, A. K. ; Zweckstetter, M.DZNE* ; Landau, M.

2026
eLife Sciences Publications Cambridge

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Please use a persistent id in citations: doi:10.7554/eLife.109290

Abstract: Amyloid-forming peptides are increasingly recognized as dynamic regulators at the host-pathogen interface, yet how environmental factors control their assembly and activity remains poorly understood. Here, RNA acts as a concentration-dependent regulator of two sequence-related α-helical peptides with fundamentally different assembly behaviors: the cross-α amyloid-forming Staphylococcus aureus virulence factor PSMα3 and the non-amyloidogenic human host-defense peptide LL-37. RNA drives PSMα3 through distinct assembly states, from liquid-like condensates to fibrillar polymorphs, while preserving cytotoxic and antimicrobial activity over time. In contrast, RNA attenuates LL-37 cytotoxicity toward host cells while maintaining antibacterial activity, consistent with a host-protective immunomodulatory effect. Together with the opposing effects of epigallocatechin gallate, which redirects both peptides into amorphous assemblies, these findings support a mechanistic model in which biological activity is governed by supramolecular architecture, assembly trajectory, and dynamics rather than by monomer abundance or mature fibrils alone. More broadly, our findings identify RNA as an environmental regulator of α-helical peptide assemblies, and establish assembly-state control as a tunable determinant of virulence and host defense.

Keyword(s): Humans (MeSH) ; Staphylococcus aureus: pathogenicity (MeSH) ; Staphylococcus aureus: metabolism (MeSH) ; Cathelicidins (MeSH) ; RNA: metabolism (MeSH) ; Antimicrobial Cationic Peptides: metabolism (MeSH) ; Antimicrobial Cationic Peptides: chemistry (MeSH) ; Amyloid: metabolism (MeSH) ; Amyloid: chemistry (MeSH) ; Virulence Factors: metabolism (MeSH) ; Virulence Factors: chemistry (MeSH) ; Protein Aggregates (MeSH) ; PSMs ; RNA ; S. aureus ; amyloid ; fibrils ; host defense ; human ; infectious disease ; microbiology ; molecular biophysics ; structural biology ; virulence ; Cathelicidins ; RNA ; Antimicrobial Cationic Peptides ; Amyloid ; Virulence Factors ; Protein Aggregates

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Contributing Institute(s):

1. Translational Structural Biology (AG Zweckstetter)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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