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- Title
Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin.
- Authors
Haun, Florian; Neumann, Simon; Peintner, Lukas; Wieland, Katrin; Habicht, Jüri; Schwan, Carsten; Østevold, Kristine; Koczorowska, Maria Magdalena; Biniossek, Martin; Kist, Matthias; Busch, Hauke; Boerries, Melanie; Davis, Roger J.; Maurer, Ulrich; Schilling, Oliver; Aktories, Klaus; Borner, Christoph
- Abstract
Anoikis is a form of apoptosis induced by cell detachment. Integrin inactivation plays a major role in the process but the exact signalling pathway is ill-defined. Here we identify an anoikis pathway using gliotoxin (GT), a virulence factor of the fungus Aspergillus fumigatus, which causes invasive aspergillosis in humans. GT prevents integrin binding to RGD-containing extracellular matrix components by covalently modifying cysteines in the binding pocket. As a consequence, focal adhesion kinase (FAK) is inhibited resulting in dephosphorylation of p190RhoGAP, allowing activation of RhoA. Sequential activation of ROCK, MKK4/MKK7 and JNK then triggers pro-apoptotic phosphorylation of Bim. Cells in suspension or lacking integrin surface expression are insensitive to GT but are sensitised to ROCK-MKK4/MKK7-JNK-dependent anoikis upon attachment to fibronectin or integrin upregulation. The same signalling pathway is triggered by FAK inhibition or inhibiting integrin αV/β3 with Cilengitide. Thus, GT can target integrins to induce anoikis on lung epithelial cells.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-05850-w