Abstract
Autophagosomes delivers cytoplasmic constituents to lysosomes for degradation, whereas inflammasomes are molecular platforms activated by infection or stress that regulate the activity of caspase-1 and the maturation of interleukin 1β (IL-1β) and IL-18. Here we show that the induction of AIM2 or NLRP3 inflammasomes in macrophages triggered activation of the G protein RalB and autophagosome formation. The induction of autophagy did not depend on the adaptor ASC or capase-1 but was dependent on the presence of the inflammasome sensor. Blocking autophagy potentiated inflammasome activity, whereas stimulating autophagy limited it. Assembled inflammasomes underwent ubiquitination and recruited the autophagic adaptor p62, which assisted their delivery to autophagosomes. Our data indicate that autophagy accompanies inflammasome activation to temper inflammation by eliminating active inflammasomes.
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Acknowledgements
We thank N. Mizushima (Tokyo Medical and Dental University) for LC3 cDNA; M. Rust for editorial assistance; and A. Fauci for support. Supported by the Intramural Research Program of the US National Institutes of Health (National Institute of Allergy and Infectious Diseases).
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C.-S.S. designed and did most of the experiments and helped write the manuscript; K.S. provided mouse macrophages and did the M. tuberculosis experiments; N.-N.H. did some of the confocal microscopy; J.K. analyzed images; M.A.-A. did the electron microscopy; K.A.F. provided the Aim2−/− cells and advice; A.S. helped in the design of several experiments and provided advice; and J.H.K. oversaw the experimental design, helped interpret the results and helped write the manuscript.
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Supplementary Text and Figures
Supplementary Figures 1–6 (PDF 622 kb)
Supplementary Video 1
NLPR3 inflammasomes co-localize with GFP-LC3. (MOV 10851 kb)
Supplementary Video 2
ASC and p62 co-localization. (MOV 10769 kb)
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Shi, CS., Shenderov, K., Huang, NN. et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13, 255–263 (2012). https://doi.org/10.1038/ni.2215
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DOI: https://doi.org/10.1038/ni.2215
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