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

• Published in: Science China. Life sciences Vol. 57; no. 5; pp. 469 - 481
• Main Authors: Qian, LiLi, Cai, ChangZu, Yuan, PengFei, Jeong, Sun-Young, Yang, XiaoZhou, DeAlmeida, Venita, Ernst, James, Costa, Michael, Cohen, Stanley N., Wei, WenSheng
• Format: Journal Article
• Language: English
• Published: Beijing Science China Press 01.05.2014; Springer Nature B.V
• Subjects: Animals; Antigens, Bacterial - toxicity; Bacterial Toxins - pharmacokinetics; Bacterial Toxins - toxicity; Biological Transport, Active; Biomedical and Life Sciences; Cell Line; Cover Article; Gene Knockdown Techniques; Gene Knockout Techniques; HEK293 Cells; HeLa Cells; Humans; Intercellular Signaling Peptides and Proteins - chemistry; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Life Sciences; Ligands; Low Density Lipoprotein Receptor-Related Protein-6 - chemistry; Low Density Lipoprotein Receptor-Related Protein-6 - metabolism; Multiprotein Complexes - chemistry; Multiprotein Complexes - metabolism; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Small Interfering - genetics; Wnt; Wnt Proteins - antagonists & inhibitors; Wnt Signaling Pathway - genetics; Wnt Signaling Pathway - physiology; 信号转导; 双向作用; 受体拮抗剂; 吸收调制; 巨噬细胞; 炭疽毒素; 生物化学分析; anthrax toxin; receptor; Kremen2; TALENs; internalization; Wnt; DKK1; LRP6
• ISSN: 1674-7305; 1869-1889
• DOI: 10.1007/s11427-014-4646-x

LRP6, a co-receptor for the morphogen Wnt, aids endocytosis of anthrax complexes. Here we report that Dickkopfl （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.