title: Inflammasome activation by altered proteostasis.
abstract: The association between altered proteostasis and inflammatory disorders has been increasingly recognized, but the underlying mechanisms are not well understood. In this study, we show that deficiency of either autophagy or sequestosome 1 (p62 or SQSTM) led to inflammasome hyperactivation in response to LPS and ATP in primary macrophages and in mice in vivo. Importantly, induction of protein misfolding by puromycin, thapsigargin, or geldanamycin resulted in inflammasome activation that was more pronounced in autophagy- or p62-deficient macrophages. Accumulation of misfolded proteins caused inflammasome activation by inducing generation of nonmitochondrial reactive oxygen species and lysosomal damage, leading to release of cathepsin B. Our results suggest that altered proteostasis results in inflammasome activation and thus provide mechanisms for the association of altered proteostasis with inflammatory disorders.
authors.affiliation: From the Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Jin Na
authors.initials: JN
authors.lastname: Shin
authors.forename: Elmoataz Abdel
authors.initials: EA
authors.lastname: Fattah
authors.forename: Abhisek
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Soyoung
authors.initials: S
authors.lastname: Ko
authors.forename: N Tony
authors.initials: NT
authors.lastname: Eissa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency; D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D002460:Cell Line; D006360:Heat-Shock Proteins / Q000172:deficiency; D006706:Homeostasis; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D002401:Cathepsin B
keywords: Autophagy; Inflammasome; Inflammation; Lysosomes; Macrophages; Protein Misfolding; Proteostasis