Journal
CELL REPORTS
Volume 18, Issue 5, Pages 1285-1297Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.01.015
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Funding
- Wellcome Trust [108246/Z/15/Z]
- Royal Society [RG130811]
- MRC
- Wellcome Trust [108246/Z/15/Z] Funding Source: Wellcome Trust
- MRC [MR/J006874/1] Funding Source: UKRI
- Medical Research Council [MR/J006874/1, 1375067] Funding Source: researchfish
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Caspase-1 activation by inflammasome signaling scaffolds initiates inflammation and antimicrobial responses. Caspase-1 proteolytically converts newly induced pro-interleukin 1 beta (IL-1 beta) into its mature form and directs its secretion, triggering pyroptosis and release of non-substrate alarmins such as interleukin 1 alpha (IL-1 alpha) and HMGB1. While some caspase-1 substrates involved in these events are known, the identities and roles of non-proteolytic targets remain unknown. Here, we use unbiased proteomics to show that the UBE2L3 ubiquitin conjugase is an indirect target of caspase-1. Caspase-1, but not caspase-4, controls pyroptosis- and ubiquitin-independent proteasomal degradation of UBE2L3 upon canonical and non-canonical inflammasome activation by sterile danger signals and bacterial infection. Mechanistically, UBE2L3 acts post-translationally to promote K48-ubiquitylation and turnover of pro-IL-1 beta and dampen mature-IL-1 beta production. UBE2L3 depletion increases pro-IL-1 beta levels and mature-IL-1 beta secretion by inflammasomes. These findings regarding UBE2L3 as a molecular rheostat have implications for IL-1-driven pathology in hereditary fever syndromes and in autoinflammatory conditions associated with UBE2L3 polymorphisms.
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