title: Bidirectional effect of Wnt signaling antagonist DKK1 on the modulation of anthrax toxin uptake.
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.
authors.affiliation: College of Life Sciences and State Key Laboratory of Protein and Plant Gene Research, Peking University, Beijing, 100871, China.
authors.forename: LiLi
authors.initials: L
authors.lastname: Qian
authors.forename: ChangZu
authors.initials: C
authors.lastname: Cai
authors.forename: PengFei
authors.initials: P
authors.lastname: Yuan
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Jeong
authors.forename: XiaoZhou
authors.initials: X
authors.lastname: Yang
authors.forename: Venita
authors.initials: V
authors.lastname: Dealmeida
authors.forename: James
authors.initials: J
authors.lastname: Ernst
authors.forename: Michael
authors.initials: M
authors.lastname: Costa
authors.forename: Stanley N
authors.initials: SN
authors.lastname: Cohen
authors.forename: WenSheng
authors.initials: W
authors.lastname: Wei
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity; D001427:Bacterial Toxins / Q000493:pharmacokinetics* / Q000633:toxicity; D001693:Biological Transport, Active; D002460:Cell Line; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C486076:KREMEN2 protein, human; C555475:LRP6 protein, human; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D051153:Wnt Proteins; C030325:anthrax toxin