cAMP Signaling by Anthrax Edema Toxin Induces Transendothelial Cell Tunnels, which Are Resealed by MIM via Arp2/3-Driven Actin Polymerization

Cell Host Microbe. 2011 Nov 17;10(5):464-74. doi: 10.1016/j.chom

B. anthracis edema toxin-mediated cAMP signaling induces transcellular tunnels
Opening of transcellular tunnels resembles the liquid dewetting phenomenon
Cells perceive newly curved membranes generated by TEMs via the I-BAR protein MIM
MIM restricts TEM opening by driving Arp2/3-dependent actin polymerization
RhoA-inhibitory bacterial toxins, such as Staphylococcus aureus EDIN toxin, induce large transendothelial cell macroaperture (TEM) tunnels that rupture the host endothelium barrier and promote bacterial dissemination. Host cells repair these tunnels by extending actin-rich membrane waves from the TEM edges. We reveal that cyclic-AMP signaling produced by Bacillus anthracis edema toxin (ET) also induces TEM formation, which correlates with increased vascular permeability. We show that ET-induced TEM formation resembles liquid dewetting, a physical process of nucleation and growth of holes within a thin liquid film. We also identify the cellular mechanisms of tunnel closure and reveal that the I-BAR domain protein Missing in Metastasis (MIM) senses de novo membrane curvature generated by the TEM, accumulates at the TEM edge, and triggers Arp2/3-dependent actin polymerization, which induces actin-rich membrane waves that close the TEM. Thus, the balance between ET-induced TEM formation and resealing likely determines the integrity of the host endothelium barrier.

Madhavi P. Maddugoda, Caroline Stefani, David Gonzalez-Rodriguez, Juha Saarikangas, Stéphanie Torrino, Sebastien Janel, Patrick Munro, Anne Doye, François Prodon, Michel Aurrand-Lions, Pierre L. Goossens, Frank Lafont, Patricia Bassereau, Pekka Lappalainen, Françoise Brochard, Emmanuel Lemichezemail

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