Signaling Cascades of the Aspergillus Fumigatus Virulence Factor Gliotoxin in Mediating Apoptosis and Invasive Aspergillosis

Résumé du livre

Abstract: Gliotoxin (GT) is the major virulence factor of the fungus Aspergillus fumigatus (A.f.) and necessary to promote invasive aspergillosis (IA) in immunocompromised patients. Disease progression requires GT-mediated loss of epithelial barrier function to allow the invasiveness of A.fumigatus. GT-induced apoptosis of epithelial cells could contribute to such function.
Here we further characterize the apoptotic signaling induced by GT. We show that GT triggers RhoA activation, which induces a kinase cascade via the Rho-associated kinase (ROCK) and the MAPK kinases MKK4/7. MKK4 and MKK7 activation precedes phosphorylation of c-Jun N-terminal kinases (JNK) and subsequent phosphorylation of Bim. Phosphorylated Bim is released from anti-apoptotic Bcl-2 and interacts with Bak to execute GT-induced apoptosis. In this context, ROCK functions as a MAPKK kinase to relay apoptotic signaling in addition to its known function on the cytoskeleton. We found that cells were resistant to GT-induced apoptosis if they were either (i) treated with JNK or ROCK inhibitors or (ii) genetically deleted or knocked-down for ROCK-1 or MKK4/7.
GT triggers cell death by a cell detachment-induced mode of apoptosis, termed anoikis. We report that GT can directly bind to cysteines in the ligand binding domain of integrin [alpha]V[beta]3. Furthermore, GT rapidly inactivates integrins to trigger anoikis. Integrin inactivation resulted in the inhibition of focal adhesion kinase (FAK) and p190RhoGAP to activate the RhoA-dependent kinase cascade. We establish GT as a novel, physiological trigger to study anoikis and integrin signaling.
Both loss of epithelial cells by apoptosis and/or cell detachment could underlie the reduced barrier integrity. Here we show that ROCK inhibitors not only block GT induced cell death but also maintain the physiological morphology by preventing detachment of bronchial epithelial cells. Pharmacological inhibition of ROCK might therefore be a promising strategy to prevent the invasive potential of A.fumigatus