Identification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin

Florian Haun, Simon Neumann, Lukas Peintner, Katrin Wieland, Jüri Habicht, Carsten Schwan, Kristine Østevold, Maria Magdalena Koczorowska, Martin Biniossek, Matthias Kist, Hauke Busch, Melanie Boerries, Roger J. Davis, Ulrich Maurer, Oliver Schilling, Klaus Aktories and Christoph Borner ()
Additional contact information
Florian Haun: Albert Ludwigs University Freiburg
Simon Neumann: Albert Ludwigs University Freiburg
Lukas Peintner: Albert Ludwigs University Freiburg
Katrin Wieland: Albert Ludwigs University Freiburg
Jüri Habicht: University Hospital Heidelberg
Carsten Schwan: Albert Ludwigs University Freiburg
Kristine Østevold: Albert Ludwigs University Freiburg
Maria Magdalena Koczorowska: Albert Ludwigs University Freiburg
Martin Biniossek: Albert Ludwigs University Freiburg
Matthias Kist: Albert Ludwigs University Freiburg
Hauke Busch: Albert Ludwigs University Freiburg
Melanie Boerries: Albert Ludwigs University Freiburg
Roger J. Davis: University of Massachusetts Medical School
Ulrich Maurer: Albert Ludwigs University Freiburg
Oliver Schilling: Albert Ludwigs University Freiburg
Klaus Aktories: Albert Ludwigs University Freiburg
Christoph Borner: Albert Ludwigs University Freiburg

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05850-w

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