Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Publication date: Available online 23 November 2016
Source:Cell Host & Microbe
Author(s): Vasilis Oikonomou, Silvia Moretti, Giorgia Renga, Claudia Galosi, Monica Borghi, Marilena Pariano, Matteo Puccetti, Carlo A. Palmerini, Lucia Amico, Alessandra Carotti, Lucia Prezioso, Angelica Spolzino, Andrea Finocchi, Paolo Rossi, Andrea Velardi, Franco Aversa, Valerio Napolioni, Luigina Romani
Defects in a form of noncanonical autophagy, known as LC3-associated phagocytosis (LAP), lead to increased inflammatory pathology during fungal infection. Although LAP contributes to fungal degradation, the molecular mechanisms underlying LAP-mediated modulation of inflammation are unknown. We describe a mechanism by which inflammation is regulated during LAP through the death-associated protein kinase 1 (DAPK1). The ATF6/C/EBP-β/DAPK1 axis activated by IFN-γ not only mediates LAP to Aspergillus fumigatus but also concomitantly inhibits Nod-like receptor protein 3 (NLRP3) activation and restrains pathogenic inflammation. In mouse models and patient samples of chronic granulomatous disease, which exhibit defective autophagy and increased inflammasome activity, IFN-γ restores reduced DAPK1 activity and dampens fungal growth. Additionally, in a cohort of hematopoietic stem cell-transplanted patients, a genetic DAPK1 deficiency is associated with increased inflammation and heightened aspergillosis susceptibility. Thus, DAPK1 is a potential drugable player in regulating the inflammatory response during fungal clearance initiated by IFN-γ.

Graphical abstract

Teaser

Defects in noncanonical autophagy increase inflammatory pathology during fungal infection. Oikonomou et al. find that the kinase DAPK1 induced by IFN-γ promotes both noncanonical autophagy and NLRP3 inflammasome proteasomal degradation in response to Aspergillus fumigatus. By restoring DAPK1, IFN-γ may assist fungal clearance while restraining inflammation in mice and humans.


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