The Atypical Ubiquitin E2 Conjugase UBE2L3 Is an Indirect Caspase-1 Target and Controls IL-1β Secretion by Inflammasomes

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Matthew J.G. Eldridge, Julia Sanchez-Garrido, Gil Ferreira Hoben, Philippa J. Goddard, Avinash R. Shenoy
Caspase-1 activation by inflammasome signaling scaffolds initiates inflammation and antimicrobial responses. Caspase-1 proteolytically converts newly induced pro-interleukin 1 beta (IL-1β) into its mature form and directs its secretion, triggering pyroptosis and release of non-substrate alarmins such as interleukin 1 alpha (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 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-1β and dampen mature-IL-1β production. UBE2L3 depletion increases pro-IL-1β levels and mature-IL-1β 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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Teaser

Eldridge et al. show that the UBE2L3 ubiquitin E2 conjugating enzyme is targeted for proteasomal degradation by inflammasomes and is therefore an indirect target of human and mouse caspase-1. They also find that UBE2L3 is a post-translational regulator of pro-IL-1β protein levels and thus regulates mature IL-1β production.


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