title: Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1.
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.
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Oikonomou
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Renga
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Galosi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Borghi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Pariano
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Puccetti
authors.affiliation: Department of Agriculture, Food, and Environmental Sciences, University of Perugia, 06132 Perugia, Italy.
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Palmerini
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Amico
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Carotti
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, 43126 Parma, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Prezioso
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, 43126 Parma, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Spolzino
authors.affiliation: Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, 00146 Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Finocchi
authors.affiliation: Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, 00146 Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.affiliation: Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Velardi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, 43126 Parma, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Aversa
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Napolioni
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy. Electronic address: luigina.romani@unipg.it.
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology*; D002460:Cell Line; D064550:Death-Associated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005658:Fungi / Q000378:metabolism* / Q000472:pathogenicity; D015966:Gene Expression Regulation, Fungal; D006105:Granulomatous Disease, Chronic / Q000382:microbiology; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D000070576:NLR Proteins / Q000187:drug effects; D010587:Phagocytosis; D010588:Phagosomes; D000067996:RAW 264.7 Cells / Q000187:drug effects / Q000382:microbiology; D013172:Spores, Fungal / Q000378:metabolism
chemical_list: D000070576:NLR Proteins; D007371:Interferon-gamma; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse; D064550:Death-Associated Protein Kinases