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

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 descr...

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Veröffentlicht in:Cell host & microbe 2016-12, Vol.20 (6), p.744-757
Hauptverfasser: Oikonomou, Vasilis, Moretti, Silvia, Renga, Giorgia, Galosi, Claudia, Borghi, Monica, Pariano, Marilena, Puccetti, Matteo, Palmerini, Carlo A., Amico, Lucia, Carotti, Alessandra, Prezioso, Lucia, Spolzino, Angelica, Finocchi, Andrea, Rossi, Paolo, Velardi, Andrea, Aversa, Franco, Napolioni, Valerio, Romani, Luigina
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •IFN-γ restrains inflammation during fungal clearance via DAPK1•DAPK1 promotes noncanonical autophagy and NLRP3 proteasomal degradation•DAPK1 deficiency predicts infection and inflammation in CGD or transplanted patients•IFN-γ therapy restores defective DAPK1 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.
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2016.10.012