Science China Life Sciences

, Volume 57, Issue 5, pp 469–481

Bidirectional effect of Wnt signaling antagonist DKK1 on the modulation of anthrax toxin uptake

  • LiLi Qian
  • ChangZu Cai
  • PengFei Yuan
  • Sun-Young Jeong
  • XiaoZhou Yang
  • Venita DeAlmeida
  • James Ernst
  • Michael Costa
  • Stanley N. Cohen
  • WenSheng Wei
Open Access
Cover Article

DOI: 10.1007/s11427-014-4646-x

Cite this article as:
Qian, L., Cai, C., Yuan, P. et al. Sci. China Life Sci. (2014) 57: 469. doi:10.1007/s11427-014-4646-x

Abstract

LRP6, a co-receptor for the morphogen Wnt, aids endocytosis of anthrax complexes. Here we report that Dickkopf1 (DKK1) protein, a secreted LRP6 ligand and antagonist, is also a modulator of anthrax toxin sensitivity. shRNA-mediated gene silencing or TALEN-mediated gene knockout of DKK1 reduced sensitivity of cells to PA-dependent hybrid toxins. However, unlike the solely inhibitory effect on Wnt signaling, the effects of DKK1 overexpression on anthrax toxicity were bidirectional, depending on its endogenous expression and cell context. Fluorescence microscopy and biochemical analyses showed that DKK1 facilitates internalization of anthrax toxins and their receptors, an event mediated by DKK1-LRP6-Kremen2 complex. Monoclonal antibodies against DKK1 provided dose-dependent protection to macrophages from killing by anthrax lethal toxin (LT). Our discovery that DKK1 forms ternary structure with LRP6 and Kremen2 in promoting PA-mediated toxin internalization provides a paradigm for bacterial exploitation of mechanisms that host cells use to internalize signaling proteins.

Keywords

DKK1 anthrax toxin LRP6 TALENs internalization Kremen2 receptor Wnt 

Copyright information

© The Author(s) 2014

Authors and Affiliations

  • LiLi Qian
    • 1
  • ChangZu Cai
    • 1
  • PengFei Yuan
    • 1
  • Sun-Young Jeong
    • 2
  • XiaoZhou Yang
    • 1
  • Venita DeAlmeida
    • 4
  • James Ernst
    • 5
  • Michael Costa
    • 4
  • Stanley N. Cohen
    • 2
    • 3
  • WenSheng Wei
    • 1
  1. 1.College of Life Sciences and State Key Laboratory of Protein and Plant Gene ResearchPeking UniversityBeijingChina
  2. 2.Department of GeneticsStanford University School of MedicineStanfordUSA
  3. 3.Department of MedicineStanford University School of MedicineStanfordUSA
  4. 4.Department of Cancer TargetsGenentech, Inc.South San FranciscoUSA
  5. 5.Department of Protein Chemistry and Protein EngineeringGenentech, Inc.South San FranciscoUSA

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