RNA selectively modulates virulent amyloid PSMα3 and host-defense LL-37 activity via phase separation
Background
Amyloid-forming peptides are increasingly recognized as crucial regulators at the host-pathogen interface, yet the precise mechanisms by which environmental factors control their assembly and biological activity remain poorly understood. Specifically, the Staphylococcus aureus virulence factor PSMα3 forms cross-α amyloids, contributing to bacterial pathogenicity, while the human host-defense peptide LL-37 is a non-amyloidogenic antimicrobial peptide with immunomodulatory roles. Understanding how their distinct assembly behaviors are modulated by environmental cues is critical for developing strategies against bacterial infections and modulating host immunity.
Study Design
Researchers investigated the concentration-dependent effects of RNA on the assembly and activity of two α-helical peptides: PSMα3 (a S. aureus virulence factor) and LL-37 (a human host-defense peptide). The study utilized various biophysical techniques to characterize peptide assembly states, including the formation of liquid-like condensates and fibrillar polymorphs. They assessed the peptides' cytotoxic activity towards host cells and their antimicrobial activity against bacteria. For comparison, they also examined the effects of epigallocatechin gallate (EGCG), a known modulator of amyloid aggregation, on both peptides.
Results
RNA was found to drive PSMα3 through distinct assembly states, transitioning from liquid-like condensates to fibrillar polymorphs. Crucially, this modulation by RNA preserved both the cytotoxic and antimicrobial activity of PSMα3 over time. In stark contrast, RNA exhibited a differential effect on LL-37, significantly attenuating its cytotoxicity towards host cells while maintaining its robust antibacterial activity. This suggests a host-protective immunomodulatory effect for LL-37 when modulated by RNA. The study also compared these effects with epigallocatechin gallate, which redirected both peptides into amorphous assemblies, demonstrating opposing outcomes.
These findings strongly support a mechanistic model where biological activity is governed by the peptide's supramolecular architecture, assembly trajectory, and dynamics, rather than solely by monomer abundance or the presence of mature fibrils. This highlights RNA as a key environmental regulator of α-helical peptide assemblies.
Key Findings
- RNA drives PSMα3 assembly through liquid-like condensates to fibrillar polymorphs, preserving its cytotoxic and antimicrobial activity.
- RNA attenuates LL-37 cytotoxicity towards host cells while maintaining its antibacterial activity, suggesting a host-protective effect.
- Epigallocatechin gallate (EGCG) redirects both PSMα3 and LL-37 into amorphous assemblies, showing opposing effects to RNA.
- Peptide biological activity is governed by supramolecular architecture, assembly trajectory, and dynamics, not just monomer abundance or mature fibrils.
Why It Matters
This research unveils RNA as a novel environmental regulator of peptide assembly, offering a new lens through which to understand and potentially manipulate virulence and host defense. Tuning peptide assembly states could become a therapeutic strategy, for instance, by designing RNA-based interventions to disarm bacterial virulence factors like PSMα3 or to enhance the host-protective aspects of peptides like LL-37 without compromising their antimicrobial efficacy. This mechanistic insight moves beyond simply targeting peptide abundance, suggesting that controlling the form of peptide aggregates could be a powerful approach in infectious disease and immunomodulation. While currently an in vitro finding, it lays groundwork for future in vivo studies exploring RNA-peptide interactions in therapeutic contexts.
rna
psmalpha3
ll-37
amyloid
host-defense
virulence