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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)744-757
Number of pages14
JournalCell Host and Microbe
Volume20
Issue number6
DOIs
Publication statusPublished - Dec 14 2016

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Death-Associated Protein Kinases
Autophagy
Phagocytosis
Inflammation
Inflammasomes
Chronic Granulomatous Disease
Aspergillus fumigatus
Aspergillosis
Mycoses
Hematopoietic Stem Cells
Pathology
Growth
Proteins

Keywords

  • Journal Article

Cite this

Oikonomou, V., Moretti, S., Renga, G., Galosi, C., Borghi, M., Pariano, M., ... Romani, L. (2016). Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1. Cell Host and Microbe, 20(6), 744-757. https://doi.org/10.1016/j.chom.2016.10.012

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

In: Cell Host and Microbe, Vol. 20, No. 6, 14.12.2016, p. 744-757.

Research output: Contribution to journalArticle

Oikonomou, V, Moretti, S, Renga, G, Galosi, C, Borghi, M, Pariano, M, Puccetti, M, Palmerini, CA, Amico, L, Carotti, A, Prezioso, L, Spolzino, A, Finocchi, A, Rossi, P, Velardi, A, Aversa, F, Napolioni, V & Romani, L 2016, 'Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1', Cell Host and Microbe, vol. 20, no. 6, pp. 744-757. https://doi.org/10.1016/j.chom.2016.10.012
Oikonomou V, Moretti S, Renga G, Galosi C, Borghi M, Pariano M et al. Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1. Cell Host and Microbe. 2016 Dec 14;20(6):744-757. https://doi.org/10.1016/j.chom.2016.10.012
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. / Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1. In: Cell Host and Microbe. 2016 ; Vol. 20, No. 6. pp. 744-757.
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AU - Oikonomou, Vasilis

AU - Moretti, Silvia

AU - Renga, Giorgia

AU - Galosi, Claudia

AU - Borghi, Monica

AU - Pariano, Marilena

AU - Puccetti, Matteo

AU - Palmerini, Carlo A.

AU - Amico, Lucia

AU - Carotti, Alessandra

AU - Prezioso, Lucia

AU - Spolzino, Angelica

AU - Finocchi, Andrea

AU - Rossi, Paolo

AU - Velardi, Andrea

AU - Aversa, Franco

AU - Napolioni, Valerio

AU - Romani, Luigina

N1 - Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2016/12/14

Y1 - 2016/12/14

N2 - 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.

AB - 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.

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