Dataset Information

The inflammasome-activated cytokine IL-1 is targeted for ubiquitylation and proteasomal degradation to limit its inflammatory potential

ABSTRACT: Interleukin-1B (IL-1B) is pathologically activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in wide-spread diseases. Therefore, IL-1B activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here we report that, relative to other inflammasome components, IL-1B is rapidly turned over by the proteasome and this correlates with its decoration by K11-, K63- and K48-linked ubiquitin chains. This IL-1 degradation signal is not only a feature of inflammasome priming but is also triggered upon inflammasome activation. We demonstrate that IL-1 K133 is modified by ubiquitin and forms a salt bridge with IL-1B D129. Loss of IL-1 K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1Bprotein levels. Accordingly, IL-1B K133R/K133R mice display increased precursor IL-1Bupon inflammasome priming and increased bioactive IL-1B following inflammasome activation, both in vitro and following LPS injection in vivo. These findings reveal new mechanisms for limiting IL-1B activity and safeguarding against damaging inflammation.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Laura Dagley

LAB HEAD: James Vince

PROVIDER: PXD021305 | Pride | 2021-04-01

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	P3042_IL1bNFLAG_01.zip	Other
	P3042_IL1bNFLAG_01_01.zip	Other
	P3042_IL1bNFLAG_02_01.zip	Other
	P3042_IL1bNFLAG_03_01.zip	Other
	P3042_IL1bNFLAG_04_01.zip	Other

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Publications

The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation.

Vijayaraj Swarna L SL Feltham Rebecca R Rashidi Maryam M Frank Daniel D Liu Zhengyang Z Simpson Daniel S DS Ebert Gregor G Vince Angelina A Herold Marco J MJ Kueh Andrew A Pearson Jaclyn S JS Dagley Laura F LF Murphy James M JM Webb Andrew I AI Lawlor Kate E KE Vince James E JE

Nature communications 20210511 1

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 degradatio ...[more]

PMID: 33976225

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