Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction

Chong-Shan Shi, National Institutes of Health
Kevin Shenderov, National Institute of Allergy and Infectious Diseases
Ning-Na Huang, National Institutes of Health
Juraj Kabat, National Institutes of Health
Abu-Asab Mones, National Institutes of Health
Katherine A. Fitzgerald, University of Massachusetts Medical School
Alan Sher, National Institutes of Health
John H. Kehrl, National Institutes of Health

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 1beta (IL-1beta) 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.