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F-actin dampens NLRP3 inflammasome activity via Flightless-I and LRRFIP2

Published in Scientific Reports. 2016, vol. 6, p. 29834
Abstract NLRP3 and ASC are able to form a large multimeric complex called in ammasome in response to a number danger signals. The NLRP3 in ammasome is required for the activation of caspase-1 and subsequent maturation of pro-IL-1β into active IL-1β. Although the mechanisms regulating the formation and activity of NLRP3 in ammasome are yet not fully elucidated, data suggest that the assembly of NLRP3 in ammasome requires microtubules to induce the proximity of ASC and NLRP3. In this study we show that micro laments (F-actin) inhibit NLRP3 in ammasome activity and interact with NLRP3 and ASC. We demonstrate that the inhibition depends on the actin polymerization state but not on the active polymerization process. In ATP- or nigericin-activated macrophages, our data further indicate that Flightless-I (FliI) and leucine-rich repeat FliI-interaction protein 2 (LRRFIP2) are required for the co-localization of NLRP3, ASC and F-actin. We also established that the ability of Ca2+ to accentuate the activity of NLRP3 in ammasome is abrogated in FliI- and LRRFIP2-knockdown macrophages, suggesting that Ca2+ signaling requires the presence of FliI and LRRFIP2. Accordingly, we observed that Ca2+/FliI-dependent severing of F-actin suppresses F-actin/FliI/LRRFIP2-dependent NLRP3 in ammasome inhibition leading to increase IL-1β production. Altogether, our results unveil a new function of F-actin in the regulation of NLRP3 in ammasome activity strengthening the importance of cytoskeleton in the regulation of in ammation.
PMID: 27431477
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Research group Inflammation et allergie (874)
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BURGER, Danielle et al. F-actin dampens NLRP3 inflammasome activity via Flightless-I and LRRFIP2. In: Scientific Reports, 2016, vol. 6, p. 29834. doi: 10.1038/srep29834 https://archive-ouverte.unige.ch/unige:86248

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Deposited on : 2016-08-22

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