| First Author | Eldridge MJG | Year | 2017 |
| Journal | Cell Rep | Volume | 18 |
| Issue | 5 | Pages | 1285-1297 |
| PubMed ID | 28147281 | Mgi Jnum | J:333638 |
| Mgi Id | MGI:6835422 | Doi | 10.1016/j.celrep.2017.01.015 |
| Citation | Eldridge MJG, et al. (2017) The Atypical Ubiquitin E2 Conjugase UBE2L3 Is an Indirect Caspase-1 Target and Controls IL-1beta Secretion by Inflammasomes. Cell Rep 18(5):1285-1297 |
| abstractText | Caspase-1 activation by inflammasome signaling scaffolds initiates inflammation and antimicrobial responses. Caspase-1 proteolytically converts newly induced pro-interleukin 1 beta (IL-1beta) into its mature form and directs its secretion, triggering pyroptosis and release of non-substrate alarmins such as interleukin 1 alpha (IL-1alpha) 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-1beta and dampen mature-IL-1beta production. UBE2L3 depletion increases pro-IL-1beta levels and mature-IL-1beta 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. |
