Caspase-1 activation by inflammasome signalling scaffolds
initiates inflammation and antimicrobial responses. Caspase-1 proteolytically converts newly induced pro-IL-1α into its mature form
and directs its secretion, triggers pyroptosis and the release of non-substrate alarmins such as IL-1α 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 report using unbiased proteomics that the UBE2L3 ubiquitin conjugase is
an indirect target of caspase-1. Caspase-1, but not caspase-4, control
led pyroptosis-and ubiquitin-independent proteasomal degradation of UBE2L3 upon canonical and non-canonical inflammasome activation by sterile danger signals and bacterial infection. Mechanistically,
UBE2L3 acted post-translationally to promote K48-ubiquitylation and
turnover of pro-IL-1β and dampen mature-IL-1β production.
UBE2L3 depletion increased pro-IL-1β levels and mature-IL-1β
secretion by inflammasomes. These findings on UBE2L3 as a molecular rheostat have implications for IL-1-driven pathology in hereditary fever syndromes, and autoinflammatory conditions associated with UBE2L3 polymorphisms.