Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance.
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Date
2021-06-07Author
Garcia, LR
Tenev, T
Newman, R
Haich, RO
Liccardi, G
John, SW
Annibaldi, A
Yu, L
Pardo, M
Young, SN
Fitzgibbon, C
Fernando, W
Guppy, N
Kim, H
Liang, L-Y
Lucet, IS
Kueh, A
Roxanis, I
Gazinska, P
Sims, M
Smyth, T
Ward, G
Bertin, J
Beal, AM
Geddes, B
Choudhary, JS
Murphy, JM
Aurelia Ball, K
Upton, JW
Meier, P
Type
Journal Article
Metadata
Show full item recordAbstract
Necroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.
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Subject
Cells, Cultured
Cell Line
HT29 Cells
NIH 3T3 Cells
Skin
Animals
Mice, Inbred C57BL
Mice, Knockout
Humans
Mice
Muromegalovirus
Herpesviridae Infections
Necrosis
Protein Kinases
Lysine
Ubiquitination
HEK293 Cells
Necroptosis
Research team
Cell Death and Immunity
Functional Proteomics Group
Cell Death and Immunity
Functional Proteomics Group
Language
eng
Date accepted
2021-04-29
License start date
2021-06-07
Citation
Nature communications, 2021, 12 (1), pp. 3364 - ?
Publisher
NATURE PORTFOLIO