Journal
EMBO REPORTS
Volume 19, Issue 10, Pages -Publisher
WILEY
DOI: 10.15252/embr.201744766
Keywords
deubiquitination; inflammasome; macrophages; USP47; USP7
Categories
Funding
- Sir Henry Dale Fellowship - Wellcome Trust [104192/Z/14/Z]
- Sir Henry Dale Fellowship - Royal Society [104192/Z/14/Z]
- Manchester Collaborative Centre for Inflammation Research, a joint initiative of the University of Manchester
- AstraZeneca
- GlaxoSmithKline
- Medical Research Council (MRC) [MR/ N029992/1]
- BBSRC
- Wellcome Trust
- University of Manchester Strategic Fund
- MRC [MR/N029992/1] Funding Source: UKRI
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The assembly and activation of the inflammasomes are tightly regulated by post-translational modifications, including ubiquitin. Deubiquitinases (DUBs) counteract the addition of ubiquitin and are essential regulators of immune signalling pathways, including those acting on the inflammasome. How DUBs control the assembly and activation of inflammasomes is unclear. Here, we show that the DUBs USP7 and USP47 regulate inflammasome activation in macrophages. Chemical inhibition of USP7 and USP47 blocks inflammasome formation, independently of transcription, by preventing ASC oligomerisation and speck formation. We also provide evidence that the ubiquitination status of NLRP3 itself is altered by inhibition of USP7 and USP47. Interestingly, we found that the activity of USP7 and USP47 increased in response to inflammasome activators. Using CRISPR/Cas9 in the macrophage cell line THP-1, we show that inflammasome activation is reduced when both USP7 and USP47 are knocked down. Altogether, these data reveal a new post-transcriptional role for USP47 and USP7 in inflammation by regulating inflammasome activation and the release of the pro-inflammatory cytokines IL-1 beta and IL-18, and implicate dual USP7 and USP47 inhibitors as potential therapeutic agents for inflammatory disease.
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