Journal article

Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance

Laura Ramos Garcia, Tencho Tenev, Richard Newman, Rachel O Haich, Gianmaria Liccardi, Sidonie Wicky John, Alessandro Annibaldi, Lu Yu, Mercedes Pardo, Samuel N Young, Cheree Fitzgibbon, Winnie Fernando, Naomi Guppy, Hyojin Kim, Lung-Yu Liang, Isabelle S Lucet, Andrew Kueh, Ioannis Roxanis, Patrycja Gazinska, Martin Sims Show all

NATURE COMMUNICATIONS | NATURE PORTFOLIO | Published : 2021

Abstract

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 ..

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Grants

Awarded by Toby Robins Research Centre


Awarded by Cancer Research UK (CRUK)


Awarded by NIH


Awarded by NHMRC


Awarded by IRIISS


Awarded by National Science Foundation


Funding Acknowledgements

The authors are indebted to J. Silke, H. Walczak, D. Komander, B.C. Bornhauser, M. GyrdHansen, P. Jat, N. Mailand and S. Wang for reagents. We thank theWEHIMAGEC Facility for the generation of the knock-in mouse. K.A.B. thanks Michael Donnelly for computational support. K.A.B. thanks the MERCURY Consortium for mentoring support. We also thank members of the Meier lab for helpful discussions. Work in the Meier lab is funded by Breast Cancer Now as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre (CTR-QR14-007) and postgraduate studentships from Cancer Research UK (CRUK; CRM089X). We thank the Breast Cancer Now Toby Robins Research Centre Nina Barough Pathology Core Facility for pathology support. J.W.U. is supported by NIH AI135709, and J.M.M. is funded by NHMRC fellowship (1105754 and 1172929), project (1124735) and IRIISS (9000587) support and the Victorian Government Operational Infrastructure Support scheme. This work was supported by National Science Foundation (https://www.nsf.gov/) award MCB-1852677 to K.A.B. We acknowledge NHS funding to the NIHR Biomedical Research Centre.