title: Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.
abstract: Cathelicidins are short cationic host defense peptides and play a central role in host innate immune system. Here we identified two novel cathelicidins, Cl-CATH2 and 3, from Columba livia. Evolutionary analysis of avian cathelicidins via phylogenetic tree and Ka/Ks calculations supported the positive selection that prompted evolution of CATH2 to CATH1 and 3, which originate from common ancestor and could belong to one superfamily. Cl-CATH2 and 3 both adopt amphipathic α-helical comformations identified by circular dichroism and the 3D structures built by Rosetta. Cl-CATH2 of CATH2 family with the most expression abundance in bird, exhibited relatively weak antimicrobial activity, but acted instead on the innate immune response without showing undesirable toxicities. In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways. Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway. Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Haining
authors.initials: H
authors.lastname: Yu
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Qiao
authors.affiliation: College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123 China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wei
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Fu
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Cai
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhong
authors.affiliation: College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123 China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001483:Base Sequence; D005075:Biological Evolution; D054804:Cathelicidins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002942:Circular Dichroism; D010856:Columbidae / Q000276:immunology*; D018076:DNA, Complementary / Q000235:genetics; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010802:Phylogeny; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D054804:Cathelicidins; D018076:DNA, Complementary; D051197:Toll-Like Receptor 4; D052247:Nitric Oxide Synthase Type II