Inflammasome Activation by Altered Proteostasis

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...

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Bibliographic Details
Published in:The Journal of biological chemistry 2013-12, Vol.288 (50), p.35886-35895
Main Authors: Shin, Jin Na, Fattah, Elmoataz Abdel, Bhattacharya, Abhisek, Ko, Soyoung, Eissa, N. Tony
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - deficiency
Animals
Autophagy
Carrier Proteins - metabolism
Cathepsin B - metabolism
Cell Line
Heat-Shock Proteins - deficiency
Homeostasis
Humans
Immunology
Inflammasome
Inflammasomes - metabolism
Inflammation
Lysosomes
Lysosomes - metabolism
Macrophages
Macrophages - cytology
Macrophages - metabolism
Mice
NLR Family, Pyrin Domain-Containing 3 Protein
Protein Folding
Protein Misfolding
Proteostasis
Reactive Oxygen Species - metabolism
Sequestosome-1 Protein
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Summary: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. Background: The mechanisms for association of altered proteostasis and inflammation are not known. Results: The deficiency of either autophagy or p62 led to inflammasome hyperactivation. Conclusion: Accumulation of misfolded proteins caused inflammasome activation by inducing generation of nonmitochondrial ROS and lysosomal damage. Significance: Our results suggest that altered proteostasis results in inflammasome activation and thus provide mechanisms for the association of altered proteostasis with inflammatory disorders.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.514919