The Ubiquitylation of IL-1β Limits Its Cleavage by Caspase-1 and Targets It for Proteasomal Degradation

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 12

PMID 33976225

Citations 33

Authors

Swarna L Vijayaraj

Rebecca Feltham

Maryam Rashidi

Daniel Frank

Zhengyang Liu

Daniel S Simpson

Gregor Ebert

Angelina Vince

Marco J Herold

Andrew Kueh

Jaclyn S Pearson

Laura F Dagley

James M Murphy

Andrew I Webb

Kate E Lawlor

James E Vince

Affiliations

Soon will be listed here.

Abstract

Interleukin-1β (IL-1β) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in a variety of other inflammatory diseases. Therefore, IL-1β activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here, we show that precursor IL-1β is rapidly turned over by the proteasome and this correlates with its decoration by K11-linked, K63-linked and K48-linked ubiquitin chains. The ubiquitylation of IL-1β is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1β cleavage by caspase-1. IL-1β K133 is modified by ubiquitin and forms a salt bridge with IL-1β D129. Loss of IL-1β K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1β. Accordingly, Il1b mice have increased levels of precursor IL-1β upon inflammasome priming and increased production of bioactive IL-1β, both in vitro and in response to LPS injection. These findings identify mechanisms that can limit IL-1β activity and safeguard against damaging inflammation.

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