Figure 1.

Schematic representation of major phagocyte modulation pathway induced by gliotoxin from fungal: spore internalization by phagocytes is an essential mechanism to prevent hyphae formation by pathogenic fungi. Gliotoxin triggers (1) F-actin disorganization, inhibition of phagocytosis by deregulation of PtdIns (3,4,5)P3 turnover, resulting in integrin and actin cytoskeleton dysfunction, preventing pseudopodia emission (2). Gliotoxin also blocks translocation of cytosolic phox proteins (p40, p67, p47) that bind to membrane proteins of phagolysosomes, gp91 and p22 to form NADPH oxidase, inhibiting reactive oxygen species (ROS) formation (3). Dectin-1-mediated ubiquitin chain formation (4) and NF-κB activity (5) are negatively modulated by gliotoxin. Phosphorylation of IκBα leads to its ubiquitination and proteasomal degradation (6). Active heterodimer p50-p65 is then released and translocated to the nucleus (7), binds to specific κB sites and either alone or in combination with other transcription factors, activates NF-κB target gene expression of the innate (8) and inflammatory immune response (9).