The Atypical Ubiquitin E2 Conjugase UBE2L3 Is an Indirect Caspase-1 Target and Controls IL-1β Secretion by Inflammasomes.
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.
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
Matthew J G
MJG
Eldridge
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
Julia
J
Sanchez-Garrido
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
Gil Ferreira
GF
Hoben
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
Philippa J
PJ
Goddard
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK. Electronic address: a.shenoy@imperial.ac.uk.
Avinash R
AR
Shenoy
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D021381:Protein Transport / Q000502:physiology; D040901:Proteomics; D015398:Signal Transduction / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*
D058847:Inflammasomes; D053583:Interleukin-1beta; D025801:Ubiquitin; C117188:Ube2l3 protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D020170:Caspase 1
IL-1β; Listeria; Salmonella; UBE2L3; caspase-1; caspase-4; commensals; inflammasomes; proteasome; ubiquitin