The atypical ubiquitin E2 conjugase UBE2L3 is an indirect Caspase-1 target and controls IL-1b secretion by Inflammasomes

Matthew J.G. Eldridge,Julia Sanchez-Garrido,Gil Ferreira Hoben, Philippa J. Goddard, Avinash R. Shenoy

Cell Reports 18, 1285–1297 January 31, 2017

Speaker: Hsiang-Ning Chang (張翔甯)                Time: 13:00~1400, May 10th, 2017

Commentator: Pei-Jane Tsai (蔡佩珍老師)         Place: Room 601

Abstract:

Recently, it was discovered that deregulating the inflammasome signaling pathway can lead to auto-inflammation, type 1 diabetes, enterocolitis and psoriasis. It has also been known that hereditary monogenic fever syndrome is driven by caspase-1 and IL-1b [1]. As caspase-1 has protease activity, previous studies have used peptide-centric proteomics approaches to identify its substrates. Caspase-7, NOX2 NADPH oxidase, glycolytic enzymes, and gasdermin-D, have all been identified as caspase-1 substrates [2]. In this study the authors initially hypothesized that UBE2L3, the ubiquitin-conjugating enzyme E2 L3, is a substrate of caspase-1. First, they used ATP and Nigericin to activate the inflammasome, and they found out that UBE2L3 could be depleted under the activation of both canonical and non-canonical inflammasome. Next, the authors wanted to determine if depletion of UBE2L3 is dependent on pyroptosis. When they used glycine to block pyroptosis, they did not observe the depletion of UBE2L3. Next, they wanted to know whether UBE2L3 is directly associated with caspase-1, yet they found out that UBE2L3 is indirectly associated with caspase-1 activation under immunofluorescence analyses. Further, sustaining the expression of UBE2L3 resulted in a decrease in pro-IL-1 b levels by ubiquitylation of residue K48 and a decline in mature IL-1 b expression. Furthermore, UBE2L3 depletion increased pro-IL-1 b levels and mature-IL-1 bsecretion in a pyroptosis-independent, and proteasome-dependent manner. This process was found to be caspase-1-dependent inflammasome. Results of this study suggested that in the future, regulating the expression of the UBE2L3 could be a therapeutic strategy for t caspase-1 dependent inflammasome associated diseases.

References:

1.         Broderick, L., De Nardo, D., Franklin, B.S., Hoffman, H.M., and Latz, E.(2015) The inflammasomes and autoinflammatory syndromes. Annu. Rev. Pathol. 10, 395–424.

2.         Agard, N.J., Maltby, D., and Wells, J.A. (2010). Inflammatory stimuli regulate caspase substrate profiles. Mol. Cell. Proteomics 9, 880–893.