Apoptosis induced by the fungal pathogen gliotoxin requires a triple phosphorylation of Bim by JNK
Program in Molecular Medicine
Animals; Apoptosis; Apoptosis Regulatory Proteins; Aspergillus fumigatus; Gliotoxin; HEK293 Cells; Humans; MAP Kinase Kinase 4; Membrane Proteins; Mice; Phosphorylation; Proto-Oncogene Proteins; Signal Transduction
Biochemistry | Cell and Developmental Biology | Cellular and Molecular Physiology | Molecular Biology
We previously reported that gliotoxin (GT), the major virulence factor of the mold Aspergillus fumigatus causing invasive aspergillosis (IA) in immunocompromised patients, induces apoptosis in a Bak-dependent manner. The signaling pathway leading to Bak activation and subsequent mitochondrial outer membrane permeabilization (MOMP) is elusive. Here, we show that GT and the supernatant of A. fumigatus (but not its GT-defective mutant) activate the JNK pathway and require a co-operative JNK-mediated BimEL phosphorylation at three sites (S100, T112 and S114) to induce apoptosis in mouse fibroblasts, human bronchial and mouse alveolar epithelial cells. Cells (i) treated with the JNK inhibitor SP600125, (ii) deleted or knocked down for JNK1/2 or Bim or (iii) carrying the BimEL triple phosphomutant S100A/T112A/S114A instead of wild-type BimEL are similarly resistant to GT-induced apoptosis. Triple-phosphorylated BimEL is more stable, redistributes from a cytoskeletal to a membrane fraction, better interacts with Bcl-2 and Bcl-xL and more effectively activates Bak than the unphosphorylated mutant. These data indicate that JNK-mediated BimEL phosphorylation at S100, T112 and S114 constitutes a novel regulatory mechanism to activate Bim in response to apoptotic stimuli.
DOI of Published Version
Cell Death Differ. 2013 Oct;20(10):1317-29. doi: 10.1038/cdd.2013.78. Epub 2013 Jul 5. Link to article on publisher's site
Cell death and differentiation
Geissler, A.; Haun, F.; Frank, D. O.; Wieland, K.; Simon, M. M.; Idzko, M.; Davis, Roger J.; Maurer, U.; and Borner, C., "Apoptosis induced by the fungal pathogen gliotoxin requires a triple phosphorylation of Bim by JNK" (2013). University of Massachusetts Medical School Faculty Publications. 758.