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

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

doi:10.1038/s41467-021-22979-3

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

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

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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^K133R/K133R 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.

Original language	English
Article number	2713
Number of pages	16
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22979-3
Publication status	Published - Dec 2021

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10.1038/s41467-021-22979-3Licence: CC BY

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Vijayaraj, S. L., Feltham, R., Rashidi, M., Frank, D., Liu, Z., Simpson, D. S., Ebert, G., Vince, A., Herold, M. J., Kueh, A., Pearson, J. S., Dagley, L. F., Murphy, J. M., Webb, A. I., Lawlor, K. E., & Vince, J. E. (2021). The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation. Nature Communications, 12(1), Article 2713. https://doi.org/10.1038/s41467-021-22979-3

@article{e2d41c66ed434a148cff2211cc32e476,

title = "The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation",

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, Il1bK133R/K133R 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.",

author = "Vijayaraj, {Swarna L.} and Rebecca Feltham and Maryam Rashidi and Daniel Frank and Zhengyang Liu and Simpson, {Daniel S.} and Gregor Ebert and Angelina Vince and Herold, {Marco J.} and Andrew Kueh and Pearson, {Jaclyn S.} and Dagley, {Laura F.} and Murphy, {James M.} and Webb, {Andrew I.} and Lawlor, {Kate E.} and Vince, {James E.}",

note = "Funding Information: We gratefully acknowledge grant support from the National Health and Medical Research Council (NHMRC) of Australia: project grants (1145788 to J.E.V., K.E.L. and J. M.M.; 1101405 to J.E.V.; 1162765 to K.E.L.), Ideas grants (1183070 to J.E.V.; 1181089 to K.E.L.) and fellowships (1172929 to J.M.M.; 1141466 to J.E.V.). K.E.L. is an Australian Research Council (ARC) Future Fellow (FT190100266). J.S.P. is supported by an Australian NHMRC Career Development Fellowship (1159230). MJH is and NHMRC Senior Research Fellow (1156095) and supported by the Leukemia and Lymphoma Society SCOR grant 7015–18. The generation of the Il1b K133R/K133R mice used in this study was supported by the Phenomics Australia (PA) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. This work was also supported by operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000653) and the Victorian State Government Operational Infrastructure Support, Australia. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-22979-3",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

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Vijayaraj, SL, Feltham, R, Rashidi, M, Frank, D, Liu, Z, Simpson, DS, Ebert, G, Vince, A, Herold, MJ, Kueh, A, Pearson, JS, Dagley, LF, Murphy, JM, Webb, AI, Lawlor, KE & Vince, JE 2021, 'The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation', Nature Communications, vol. 12, no. 1, 2713. https://doi.org/10.1038/s41467-021-22979-3

TY - JOUR

T1 - The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation

AU - Vijayaraj, Swarna L.

AU - Feltham, Rebecca

AU - Rashidi, Maryam

AU - Frank, Daniel

AU - Liu, Zhengyang

AU - Simpson, Daniel S.

AU - Ebert, Gregor

AU - Vince, Angelina

AU - Herold, Marco J.

AU - Kueh, Andrew

AU - Pearson, Jaclyn S.

AU - Dagley, Laura F.

AU - Murphy, James M.

AU - Webb, Andrew I.

AU - Lawlor, Kate E.

AU - Vince, James E.

N1 - Funding Information: We gratefully acknowledge grant support from the National Health and Medical Research Council (NHMRC) of Australia: project grants (1145788 to J.E.V., K.E.L. and J. M.M.; 1101405 to J.E.V.; 1162765 to K.E.L.), Ideas grants (1183070 to J.E.V.; 1181089 to K.E.L.) and fellowships (1172929 to J.M.M.; 1141466 to J.E.V.). K.E.L. is an Australian Research Council (ARC) Future Fellow (FT190100266). J.S.P. is supported by an Australian NHMRC Career Development Fellowship (1159230). MJH is and NHMRC Senior Research Fellow (1156095) and supported by the Leukemia and Lymphoma Society SCOR grant 7015–18. The generation of the Il1b K133R/K133R mice used in this study was supported by the Phenomics Australia (PA) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. This work was also supported by operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000653) and the Victorian State Government Operational Infrastructure Support, Australia. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/12

Y1 - 2021/12

N2 - 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, Il1bK133R/K133R 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.

AB - 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, Il1bK133R/K133R 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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U2 - 10.1038/s41467-021-22979-3

DO - 10.1038/s41467-021-22979-3

M3 - Article

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AN - SCOPUS:85105768798

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

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ER -

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

Abstract

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Cite this

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

Abstract

Access to Document

Other files and links

Projects

Role of A1 in repressing mitochondrial apoptosis to limit pathogen clearance

Role of programmed cell death in NLRP3 inflammasome activation and Metabolic Syndrome

Unconventional mechanisms for activating the NLRP3 inflammasome

Cite this