Journal article
Oligomerization-driven MLKL ubiquitylation antagonizes necroptosis
Z Liu, LF Dagley, K Shield-Artin, SN Young, A Bankovacki, X Wang, M Tang, J Howitt, CA Stafford, U Nachbur, C Fitzgibbon, SE Garnish, AI Webb, D Komander, JM Murphy, JM Hildebrand, J Silke
EMBO Journal | Published : 2021
Abstract
Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase-independent form of programmed cell death called necroptosis. Receptor-interacting serine/threonine protein kinase 3 (RIPK3) phosphorylates MLKL, triggering MLKL oligomerization, membrane translocation and membrane disruption. MLKL also undergoes ubiquitylation during necroptosis, yet neither the mechanism nor the significance of this event has been demonstrated. Here, we show that necroptosis-specific multi-mono-ubiquitylation of MLKL occurs following its activation and oligomerization. Ubiquitylated MLKL accumulates in a digitonin-insoluble cell fraction comprising organellar and plasma membranes and protein aggregat..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
We would like to thank Jiami Han, Yueyuan Li and the WEHI mouse facility for technical assistance. This work was funded by NHMRC grants 1025594 (JS), 1046984 (JS) and 1105023 (JS and JMH) and fellowships 1172929 (JMM), 1058190 (JS), 1107149 (JS) and 110574 (JS) and was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS (9000587).