LL-37 peptide enhancement of signal transduction by Toll-like receptor 3 is regulated by pH: identification of a peptide antagonist of LL-37.
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.
['Singh|Divyendu|D|', 'Vaughan|Robert|R|', 'Kao|C Cheng|CC|']
D000595:Amino Acid Sequence D023181:Antimicrobial Cationic Peptides D001665:Binding Sites D011992:Endosomes D006801:Humans D006863:Hydrogen-Ion Concentration D008969:Molecular Sequence Data D010455:Peptides D012330:RNA, Double-Stranded D015398:Signal Transduction D051196:Toll-Like Receptor 3 D015854:Up-Regulation
pH Endosome Innate Immunity RNA-binding Protein Toll-like Receptor (TLR) pH Regulation