title: IFN-γ Induces Mimic Extracellular Trap Cell Death in Lung Epithelial Cells Through Autophagy-Regulated DNA Damage.
abstract: Treatment of interferon-γ (IFN-γ) causes cell growth inhibition and cytotoxicity in lung epithelial malignancies. Regarding the induction of autophagy related to IFN-γ signaling, this study investigated the link between autophagy and IFN-γ cytotoxicity. In A549 human lung cancer cells, IFN-γ treatment induced concurrent apoptotic and nonapoptotic events. Unexpectedly, the nonapoptotic cells present mimic extracellular trap cell death (ETosis), which was regulated by caspase-3 and by autophagy induction through immunity-related GTPase family M protein 1 and activating transcription factor 6. Furthermore, IFN-γ signaling controlled mimic ETosis through a mechanism involving an autophagy- and Fas-associated protein with death domain-controlled caspase-8/-3 activation. Following caspase-mediated lamin degradation, IFN-γ caused DNA damage-associated ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM)-regulated mimic ETosis. Upon ATR/ATM signaling, peptidyl arginine deiminase 4 (PAD4)-mediated histone 3 citrullination promoted mimic ETosis. Such IFN-γ-induced effects were defective in PC14PE6/AS2 human lung cancer cells, which were unsusceptible to IFN-γ-induced autophagy. Due to autophagy-based caspase cascade activation, IFN-γ triggers unconventional caspase-mediated DNA damage, followed by ATR/ATM-regulated PAD4-mediated histone citrullination during mimic ETosis in lung epithelial malignancy.
authors.affiliation: 1 Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan .|2 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University , Taipei, Taiwan .
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.affiliation: 3 Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University , Tainan, Taiwan .
authors.forename: Shun-Yi
authors.initials: SY
authors.lastname: Chien
authors.affiliation: 4 Translational Research Center, Taipei Medical University , Taipei, Taiwan .
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.affiliation: 5 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University , Tainan, Taiwan .
authors.forename: Chia-Yuan
authors.initials: CY
authors.lastname: Hsieh
authors.affiliation: 5 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University , Tainan, Taiwan .
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Tseng
authors.affiliation: 1 Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan .|2 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University , Taipei, Taiwan .
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Wang
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D065206:Extracellular Traps / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D019014:fas Receptor / Q000378:metabolism
chemical_list: D006657:Histones; D050856:Interferon Regulatory Factor-1; D019014:fas Receptor; D007371:Interferon-gamma; D064007:Ataxia Telangiectasia Mutated Proteins; D006867:Hydrolases; D053148:Caspase 3; D053181:Caspase 8; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases