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Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.

Yu H, Lu Y, Qiao X, Wei L, Fu T, Cai S, Wang C, Liu X, Zhong S, Wang Y - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.

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.

No MeSH data available.


Related in: MedlinePlus

Phylogenetic analyses of Cl-CATH2, Cl-CATH3 and all avian cathelicidins on the basis of the proregions.The phylogenetic dendrogram was constructed by the Neighbor-joining method based on the proportion difference of aligned amino acid sites of the sequence. Only branches supported by a bootstrap value (expressed as percentage of 1000 bootstrap samples supporting the branch) are shown at the branching points.
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f2: Phylogenetic analyses of Cl-CATH2, Cl-CATH3 and all avian cathelicidins on the basis of the proregions.The phylogenetic dendrogram was constructed by the Neighbor-joining method based on the proportion difference of aligned amino acid sites of the sequence. Only branches supported by a bootstrap value (expressed as percentage of 1000 bootstrap samples supporting the branch) are shown at the branching points.

Mentions: The multi avian cathelicidins alignment was performed on basis of the precursors. A condensed multifurcating tree was constructed, emphasizing the reliable portion of pattern branches (Fig. 2). It is demonstrated that all avian cathelicidins form two distinct clusters, with B1 family located in a separated clade from others. Families of CATH1, 2 and 3 are in the second, also the main cluster, and undoubtedly show evolutionary ‘closeness’ to each other, suggesting that CATH1~3 families arose from a common ancestor. To further probe the evolutional relationships among avian cathelicidin families, the ratio of the number of nonsynonymous substitutions per non-synonymous site (Ka) to the number of synonymous substitutions per synonymous site (Ks), the Ka/Ks ratio, was calculated for each gene domain of chicken cathelicidins individually (see Supplementary Table S2 online). The results show that B1 undoubtedly represents the oldest gene family among all, and positive selection has greatly prompted evolution of cathelicidin sequence to smaller size and better activity. Besides, it is also indicated that CATH2 has a longer evolutionary history than CATH1 and 3, which is further approved by the positive selection targeting the mature peptide domain driven by pressures of pathogen diversity and virulence, since there was a tendency that CATH1s and 3s are evidently more efficacious than CATH-2s in killing pathogens162430.


Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.

Yu H, Lu Y, Qiao X, Wei L, Fu T, Cai S, Wang C, Liu X, Zhong S, Wang Y - Sci Rep (2015)

Phylogenetic analyses of Cl-CATH2, Cl-CATH3 and all avian cathelicidins on the basis of the proregions.The phylogenetic dendrogram was constructed by the Neighbor-joining method based on the proportion difference of aligned amino acid sites of the sequence. Only branches supported by a bootstrap value (expressed as percentage of 1000 bootstrap samples supporting the branch) are shown at the branching points.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508531&req=5

f2: Phylogenetic analyses of Cl-CATH2, Cl-CATH3 and all avian cathelicidins on the basis of the proregions.The phylogenetic dendrogram was constructed by the Neighbor-joining method based on the proportion difference of aligned amino acid sites of the sequence. Only branches supported by a bootstrap value (expressed as percentage of 1000 bootstrap samples supporting the branch) are shown at the branching points.
Mentions: The multi avian cathelicidins alignment was performed on basis of the precursors. A condensed multifurcating tree was constructed, emphasizing the reliable portion of pattern branches (Fig. 2). It is demonstrated that all avian cathelicidins form two distinct clusters, with B1 family located in a separated clade from others. Families of CATH1, 2 and 3 are in the second, also the main cluster, and undoubtedly show evolutionary ‘closeness’ to each other, suggesting that CATH1~3 families arose from a common ancestor. To further probe the evolutional relationships among avian cathelicidin families, the ratio of the number of nonsynonymous substitutions per non-synonymous site (Ka) to the number of synonymous substitutions per synonymous site (Ks), the Ka/Ks ratio, was calculated for each gene domain of chicken cathelicidins individually (see Supplementary Table S2 online). The results show that B1 undoubtedly represents the oldest gene family among all, and positive selection has greatly prompted evolution of cathelicidin sequence to smaller size and better activity. Besides, it is also indicated that CATH2 has a longer evolutionary history than CATH1 and 3, which is further approved by the positive selection targeting the mature peptide domain driven by pressures of pathogen diversity and virulence, since there was a tendency that CATH1s and 3s are evidently more efficacious than CATH-2s in killing pathogens162430.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.

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.

No MeSH data available.


Related in: MedlinePlus