title: Inhibition of lethal inflammatory responses through the targeting of membrane-associated Toll-like receptor 4 signaling complexes with a Smad6-derived peptide.
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 422-441 of Smad6. Smaducin-6 interacted with Pellino-1, located in the inner membrane, thereby disrupting the formation of IRAK1-, RIP1-, IKKε-mediated TLR4 signaling complexes. Systemic administration of Smaducin-6 showed a significant therapeutic effect on mouse TLR4-mediated inflammatory disease models, cecal-ligation-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.
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Youn Sook
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Su Myung
authors.initials: SM
authors.lastname: Jung
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Sang-Doo
authors.initials: SD
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jun Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Pathology, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Kyeong Cheon
authors.initials: KC
authors.lastname: Jung
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Mizuko
authors.initials: M
authors.lastname: Mamura
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.
authors.forename: Sangho
authors.initials: S
authors.lastname: Lee
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Yoe-Sik
authors.initials: YS
authors.lastname: Bae
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea parks@skku.edu.
authors.forename: Seok Hee
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000378:metabolism; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D018805:Sepsis / Q000188:drug therapy*; D015398:Signal Transduction; D051905:Smad6 Protein / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D009687:Nuclear Proteins; D009842:Oligopeptides; D051905:Smad6 Protein; D051197:Toll-Like Receptor 4; D044767:Ubiquitin-Protein Ligases; C418046:Peli1 protein, mouse
keywords: Pellino‐1; Smad6; TLR4; inflammation; sepsis