An ancestral host defence peptide within human β-defensin 3 recapitulates the antibacterial and antiviral activity of the full-length molecule.

Ersilia Nigro,Daniela Sarnataro,Vincenzo Granata,Jonathan K Ball,Veronica Folliero,Olga Scudiero,Irene Colavita,Alfonso Carotenuto,Massimiliano Galdiero,Aurora Daniele,Francesco Salvatore,Richard A Urbanowicz,Stefania Galdiero,Gerardo Zambrano,Antonello Pessi

doi:10.1038/srep18450

Abstract

Host defence peptides (HDPs) are critical components of innate immunity. Despite their diversity, they share common features including a structural signature, designated “γ-core motif”. We reasoned that for each HDPs evolved from an ancestral γ-core, the latter should be the evolutionary starting point of the molecule, i.e. it should represent a structural scaffold for the modular construction of the full-length molecule, and possess biological properties. We explored the γ-core of human β-defensin 3 (HBD3) and found that it: (a) is the folding nucleus of HBD3; (b) folds rapidly and is stable in human serum; (c) displays antibacterial activity; (d) binds to CD98, which mediates HBD3 internalization in eukaryotic cells; (e) exerts antiviral activity against human immunodeficiency virus and herpes simplex virus; and (f) is not toxic to human cells. These results demonstrate that the γ-core within HBD3 is the ancestral core of the full-length molecule and is a viable HDP per se, since it is endowed with the most important biological features of HBD3. Notably, the small, stable scaffold of the HBD3 γ-core can be exploited to design disease-specific antimicrobial agents.

Highlights

The bacterial membranes and the cholesterol-rich eukaryotic cell membranes
We previously reported that HBD3 interacts with CD98, a type II transmembrane protein whose overexpression has been associated with increased attachment of Enteropathogenic E. coli and C. rodentium in mouse colon[31], endocytosis of vaccinia virus[53], and poor prognosis in several tumours[30,32,33], and proposed that this interaction plays an important role in the antibacterial and innate immune surveillance activity of the peptide[21]
We asked whether the γ -core motif within HBDs represents a primordial Host defence peptides (HDPs) that evolved into the full-length molecules of today

Summary

Introduction

The bacterial membranes and the cholesterol-rich eukaryotic cell membranes. The mechanistic aspects of these molecules are important aspects for their function in biological systems[5,6,7,8]. CD98 plays a regulatory role in membrane fusion mediated by the enveloped viruses Newcastle disease virus[28], human parainfluenza virus type 229, HIV30,31, and HSV32, suggesting that binding to and downregulation of CD98 by HBD3 may be an antiviral, in addition to an antibacterial, mechanism. HBD3 is a high-affinity ligand for melanocortin receptors[33,34], the biological significance of this process is unclear This pleiotropy of biological activities suggests that HBD3 may be an excellent example of the evolutionary strategy based on the γ -core[11] whereby the latter is the structural scaffold endowed with basal antimicrobial activity onto which additional α -helical and/or β -sheet domains are added in a modular fashion to improve potency and/or to exert novel functions. We report that the HBD3 γ -core peptide folds rapidly and is highly stable in human serum

Methods

Results

Conclusion