Midkine and Pleiotrophin have bactericidal properties: preserved antibacterial activity in a family of Heparin-binding growth factors during evolution
2010 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 21, 16105-16115 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2010. Vol. 285, no 21, 16105-16115 p.
human beta-defensins, antimicrobial peptides, inflammatory responses, epithelial-cells, expression, gene, protein, chemokines, cytokine, immunity
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:umu:diva-43201DOI: 10.1074/jbc.M109.081232ISI: 000277715900048OAI: oai:DiVA.org:umu-43201DiVA: diva2:412374
ISI Document Delivery No.: 596WJ Times Cited: 0 Cited Reference Count: 59 Svensson, Sara L. Pasupuleti, Mukesh Walse, Bjorn Malmsten, Martin Morgelin, Matthias Sjogren, Camilla Olin, Anders I. Collin, Mattias Schmidtchen, Artur Palmer, Ruth Egesten, Arne Swedish Research Council ; Swedish Heart and Lung Foundation ; Medical Faculty at Lund University ; Swedish Government Funds for Clinical Research ; Foundations of Bergh, Crafoord, Ihre, Hedberg, Kock, Marianne & Marcus Wallenberg, and Osterlund This work was supported by grants from the Swedish Research Council (Project 20674), the Swedish Heart and Lung Foundation (Project 20080246), the Medical Faculty at Lund University, Swedish Government Funds for Clinical Research (ALF), and the Foundations of Bergh, Crafoord, Ihre, Hedberg, Kock, Marianne & Marcus Wallenberg, and Osterlund. Amer soc biochemistry molecular biology inc Bethesda2011-04-222011-04-222011-11-04Bibliographically approved