Actin enables the antimicrobial action of LL-37 in the presence of microbial proteases [Protein Structure and Folding]

June 19th, 2014 by Sol, A., Skvirsky, Y., Nashef, R., Zelentsova, K., Burstyn-cohen, T., Blotnick, E., Muhlrad, A., Bachrach, G.

Host defense peptides play an important host-protective role by their microcidal action, immumodulatory functions and tissue repair activities. Proteolysis is a common strategy of pathogens to neutralize host defense peptides. Here we show that actin, the most abundant structural protein in eukaryotes, binds the LL-37 host defense peptide, protects it from degradation by the proteases of Pseudomonas aeruginosa and Porphyromonas gingivalis, and enables its anti-microbial activity despite the presence of the proteases. Co-localization of LL-37 with extracellular actin was observed in necrotized regions of samples from oral lesions. Competition assays, cross linking experiments, limited proteolysis and mass spectrometry revealed that LL-37 binds by specific hydrophobic interactions to the His40-Lys50 segment of actin, located in the DNase1 binding loop. The integrity of the binding site of both LL-37 and actin is a prerequisite to the binding. Our results demonstrate that actin, presumably released by dead cells and abundant in infected sites, might be utilized by the immune system to enhance spatio-temporal immunity in an attempt to arrest infection and control inflammation.