LL-37 peptide enhancement of signal transduction by Toll-like receptor 3 is regulated by pH: identification of a peptide antagonist of LL-37.
Singh. Divyendu D; Vaughan. Robert R; Kao. C Cheng CC
Key Findings
- LL‑37 binds dsRNA and enhances TLR3 signaling in a pH‑dependent manner
- LL‑37 forms larger complexes that fall apart when the environment becomes acidic
- A fragment called LL‑29 blocks LL‑37’s ability to boost TLR3 signaling and prevents its delivery to endosomes
- LL‑37’s half‑life (~1 h) is extended by inhibiting endosome acidification or cathepsin enzymes
Practical Outcomes
- For most biohackers there’s no direct protocol to apply—LL‑37 isn’t a supplement you can safely take, and the work is mostly about cellular mechanisms. The findings suggest that any future use of LL‑37 would need to consider timing, acidity, and enzyme activity, but currently it offers little actionable guidance for longevity or performance.
Summary
LL-37 is a natural human peptide that can bind double‑stranded RNA and boost a specific immune sensor (TLR3) inside cells, but it only works well in the acidic environment of endosomes and breaks apart after about an hour. A shorter piece of the peptide, LL‑29, can block this boost. Changing the acidity inside cells or stopping certain enzymes can keep LL‑37 around longer, but the study doesn’t give clear ways to use this in everyday health hacks.
Abstract
LL-37 is a peptide secreted by human epithelial cells that can lyse bacteria, suppress signaling by Toll-like receptor 4 (TLR4), and enhance signaling to double-stranded RNA (dsRNA) by TLR3. How LL-37 interacts with dsRNA to affect signal transduction by TLR3 is not completely understood. We determined that LL-37 binds dsRNA and traffics to endosomes and releases the dsRNA in a pH-dependent manner. Using dynamic light scattering spectroscopy and cell-based FRET experiments, LL-37 was found to form higher order complexes independent of dsRNA binding. Upon acidification LL-37 will dissociate from a larger complex. In cells, LL-37 has a half-live of ∼ 1 h. LL-37 half-life was increased by inhibiting endosome acidification or inhibiting cathepsins, which include proteases whose activity are activated by endosome acidification. Residues in LL-37 that contact poly(I:C) and facilitate oligomerization in vitro were mapped. Peptide LL-29, which contains the oligomerization region of LL-37, inhibited LL-37 enhancement of TLR3 signal transduction. LL-29 prevented LL-37 · poly(I:C) co-localization to endosomes containing TLR3. These results shed light on the requirements for LL-37 enhancement of TLR3 signaling.
Study Information
pubmed
2014
2014-08-04T00:00:00.000Z
10.1074/jbc.m114.582973