Cell Reports
Volume 18, Issue 5, 31 January 2017, Pages 1285-1297
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Article
The Atypical Ubiquitin E2 Conjugase UBE2L3 Is an Indirect Caspase-1 Target and Controls IL-1β Secretion by Inflammasomes

https://doi.org/10.1016/j.celrep.2017.01.015Get rights and content
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Highlights

  • Caspase-1 inflammasomes induce loss of UBE2L3 in macrophages and dendritic cells

  • UBE2L3 loss is proteasome-dependent, ubiquitin- and pyroptosis-independent

  • UBE2L3 participates in K48 ubiquitylation and proteasomal turnover of pro-IL-1β

  • UBE2L3 modulates levels of pro-IL-1β available for processing by caspase-1

Summary

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.

Keywords

inflammasomes
caspase-1
IL-1β
UBE2L3
ubiquitin
proteasome
caspase-4
Salmonella
Listeria
commensals

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