The atypical ubiquitin E2 conjugase UBE2L3 is an indirect caspase-1 target and controls IL-1beta secretion by inflammasomes

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Title: The atypical ubiquitin E2 conjugase UBE2L3 is an indirect caspase-1 target and controls IL-1beta secretion by inflammasomes
Author(s): Eldridge, MJG
Sanchez Garrido, J
Hoben, GF
Goddard, PJ
Shenoy, AR
Item Type: Journal Article
Abstract: 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.
Publication Date: 31-Jan-2017
Date of Acceptance: 19-Dec-2016
URI: http://hdl.handle.net/10044/1/43347
DOI: https://dx.doi.org/10.1016/j.celrep.2017.01.015
ISSN: 2211-1247
Publisher: Elsevier (Cell Press)
Start Page: 1285
End Page: 1297
Journal / Book Title: Cell Reports
Volume: 18
Issue: 5
Sponsor/Funder: The Royal Society
Wellcome Trust
Funder's Grant Number: RG130811
108246/Z/15/Z
Copyright Statement: ª 2017 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
NF-KAPPA-B
SYSTEMIC-LUPUS-ERYTHEMATOSUS
NLRP3 INFLAMMASOME
DIFFERENTIAL REQUIREMENT
LISTERIA-MONOCYTOGENES
LINEAR UBIQUITINATION
BACTERIAL PATHOGENS
PROTEIN COMPLEXES
GENE-EXPRESSION
CELL-DEATH
IL-1β
Listeria
Salmonella
UBE2L3
caspase-1
caspase-4
commensals
inflammasomes
proteasome
ubiquitin
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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