Midkine and Pleiotrophin Have Bactericidal Properties: Preserved Antibacterial Activity in a Family of Heparin-Binding Growth Factors During Evolution

J Biol Chem. 2010 May 21;285(21):16105-15. doi: 10.1074/jbc.M109.081232. Epub 2010 Mar 22.

Abstract

Antibacterial peptides of the innate immune system combat pathogenic microbes, but often have additional roles in promoting inflammation and as growth factors during tissue repair. Midkine (MK) and pleiotrophin (PTN) are the only two members of a family of heparin-binding growth factors. They show restricted expression during embryogenesis and are up-regulated in neoplasia. In addition, MK shows constitutive and inflammation-dependent expression in some non-transformed tissues of the adult. In the present study, we show that both MK and PTN display strong antibacterial activity, present at physiological salt concentrations. Electron microscopy of bacteria and experiments using artificial lipid bilayers suggest that MK and PTN exert their antibacterial action via a membrane disruption mechanism. The predicted structure of PTN, employing the previously solved MK structure as a template, indicates that both molecules consist of two domains, each containing three antiparallel beta-sheets. The antibacterial activity was mapped to the unordered C-terminal tails of both molecules and the last beta-sheets of the N-terminals. Analysis of the highly conserved MK and PTN orthologues from the amphibian Xenopus laevis and the fish Danio rerio suggests that they also harbor antibacterial activity in the corresponding domains. In support of an evolutionary conserved function it was found that the more distant orthologue, insect Miple2 from Drosophila melanogaster, also displays strong antibacterial activity. Taken together, the findings suggest that MK and PTN, in addition to their earlier described activities, may have previously unrealized important roles as innate antibiotics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / metabolism
  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cytokines / chemistry*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster
  • Embryonic Development / physiology
  • Evolution, Molecular*
  • Gene Expression Regulation, Developmental / physiology
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Lipid Bilayers / chemistry*
  • Lipid Bilayers / metabolism
  • Midkine
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nerve Growth Factors / chemistry*
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Peptide Mapping
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Xenopus laevis
  • Zebrafish

Substances

  • Anti-Bacterial Agents
  • Carrier Proteins
  • Cytokines
  • Drosophila Proteins
  • Lipid Bilayers
  • MDK protein, human
  • Miple2 protein, Drosophila
  • Nerve Growth Factors
  • pleiotrophin
  • Midkine