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Inhibition of lethal inflammatory responses through the targeting of membrane-associated Toll-like receptor 4 signaling complexes with a Smad6-derived peptide Seok Hee Park Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea Abstract We have previously reported that Smad6, one of the inhibitory Smads of transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signaling, inhibits Toll-like receptor (TLR) 4 signaling by disrupting the Pellino-1-mediated TLR4 signaling complex. Here we developed Smaducin-6: a novel membrane-tethered palmitic acid-conjugated Smad6-derived peptide composed of amino acids 422 to 441 of Smad6. Smaducin-6 interacted with Pellino-1, located in the inner membrane, thereby disrupted the formation of IRAK1-, RIP1-, IKKεmediated TLR4 signaling complexes. Systemic administration of Smaducin-6 showed a significant therapeutic effect on mouse TLR4-mediated inflammatory disease models, cecalligation-puncture (CLP)-induced sepsis and lipopolysaccharide-induced endotoxemia, by inhibiting pro-inflammatory cytokine production and apoptosis, while enhancing neutrophil migration and bacterial clearance. Our findings provide clues to develop new peptide-based drugs to target Pellino-1 protein in TLR4 signaling pathway for the treatment of sepsis.
