title: Intracellular receptor for human host defense peptide LL-37 in monocytes.
abstract: The human cationic host defense peptide LL-37 has a broad range of immunomodulatory, anti-infective functions. A synthetic innate defense regulator peptide, innate defense regulator 1 (IDR-1), based conceptually on LL-37, was recently shown to selectively modulate innate immunity to protect against a wide range of bacterial infections. Using advanced proteomic techniques, ELISA, and Western blotting procedures, GAPDH was identified as a direct binding partner for LL-37 in monocytes. Enzyme kinetics and mobility shift studies also indicated LL-37 and IDR-1 binding to GAPDH. The functional relevance of GAPDH in peptide-induced responses was demonstrated by using gene silencing of GAPDH with small interfering RNA (siRNA). Previous studies have established that the induction of chemokines and the anti-inflammatory cytokine IL-10 are critical immunomodulatory functions in the anti-infective properties of LL-37 and IDR-1, and these functions are modulated by the MAPK p38 pathway. Consistent with that, this study demonstrated the importance of the GAPDH interactions with these peptides since gene silencing of GAPDH resulted in impaired p38 MAPK signaling, downstream chemokine and cytokine transcriptional responses induced by LL-37 and IDR-1, and LL-37-induced cytokine production. Bioinformatic analysis, using InnateDB, of the major interacting partners of GAPDH indicated the likelihood that this protein can impact on innate immune pathways including p38 MAPK. Thus, this study has demonstrated a novel function for GAPDH as a mononuclear cell receptor for human cathelicidin LL-37 and immunomodulatory IDR-1 and conclusively demonstrated its relevance in the functioning of cationic host defense peptides.
authors: Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Neeloffer
authors: N
authors: Mookherjee
authors: Dustin N D
authors: DN
authors: Lippert
authors: Pamela
authors: P
authors: Hamill
authors: Reza
authors: R
authors: Falsafi
authors: Anastasia
authors: A
authors: Nijnik
authors: Jason
authors: J
authors: Kindrachuk
authors: Jelena
authors: J
authors: Pistolic
authors: Jennifer
authors: J
authors: Gardy
authors: Pegah
authors: P
authors: Miri
authors: Misbah
authors: M
authors: Naseer
authors: Leonard J
authors: LJ
authors: Foster
authors: Robert E W
authors: RE
authors: Hancock
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000502:physiology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D034741:RNA, Small Interfering; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D054804:Cathelicidins