IL-1ß turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation.

The cytokine interleukin-1ß (IL-1ß) has pivotal roles in antimicrobial immunity, but also incites inflammatory disease. Bioactive IL-1ß is released following proteolytic maturation of the pro-IL-1ß precursor by caspase-1. UBE2L3, a ubiquitin conjugating enzyme, promotes pro-IL-1ß ubiquitylation and proteasomal disposal. However, actions of UBE2L3 in vivo and its ubiquitin ligase partners in this process are unknown. Here we report that deletion of Ube2l3 in mice reduces pro-IL-1ß turnover in macrophages, leading to excessive mature IL-1ß production, neutrophilic inflammation and disease following inflammasome activation. An unbiased RNAi screen identified TRIP12 and AREL1 E3 ligases of the Homologous to E6 C-terminus (HECT) family in adding destabilising K27-, K29- and K33- poly-ubiquitin chains on pro-IL-1ß. We show that precursor abundance determines mature IL-1ß production, and UBE2L3, TRIP12 and AREL1 limit inflammation by shrinking the cellular pool of pro-IL-1ß. Our study uncovers fundamental processes governing IL-1ß homeostasis and provides molecular insights that could be exploited to mitigate its adverse actions in disease.

Composite faces are not (necessarily) processed coactively: A test using systems factorial technology and logical-rule models.

Upright faces are thought to be processed more holistically than inverted faces. In the widely used composite face paradigm, holistic processing is inferred from interference in recognition performance from a to-be-ignored face half for upright and aligned faces compared with inverted or misaligned faces. We sought to characterize the nature of holistic processing in composite faces in computational terms. We use logical-rule models (Fific, Little, & Nosofsky, 2010) and Systems Factorial Technology (Townsend & Nozawa, 1995) to examine whether composite faces are processed through pooling top and bottom face halves into a single processing channel-coactive processing-which is one common mechanistic definition of holistic processing. By specifically operationalizing holistic processing as the pooling of features into a single decision process in our task, we are able to distinguish it from other processing models that may underlie composite face processing. For instance, a failure of selective attention might result even when top and bottom components of composite faces are processed in serial or in parallel without processing the entire face coactively. Our results show that performance is best explained by a mixture of serial and parallel processing architectures across all 4 upright and inverted, aligned and misaligned face conditions. The results indicate multichannel, featural processing of composite faces in a manner inconsistent with the notion of coactivity. (PsycINFO Database Record