Journal article

The necroptotic cell death pathway operates in megakaryocytes, but not in platelet synthesis

Diane Moujalled, Pradnya Gangatirkar, Maria Kauppi, Jason Corbin, Marion Lebois, James M Murphy, Najoua Lalaoui, Joanne M Hildebrand, John Silke, Warren S Alexander, Emma C Josefsson

Cell Death & Disease | SPRINGERNATURE | Published : 2021

Abstract

Necroptosis is a pro-inflammatory cell death program executed by the terminal effector, mixed lineage kinase domain-like (MLKL). Previous studies suggested a role for the necroptotic machinery in platelets, where loss of MLKL or its upstream regulator, RIPK3 kinase, impacted thrombosis and haemostasis. However, it remains unknown whether necroptosis operates within megakaryocytes, the progenitors of platelets, and whether necroptotic cell death might contribute to or diminish platelet production. Here, we demonstrate that megakaryocytes possess a functional necroptosis signalling cascade. Necroptosis activation leads to phosphorylation of MLKL, loss of viability and cell swelling. Analyses a..

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Grants

Awarded by National Health and Medical Research Council of Australia Project


Funding Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia Project and Program Grants (1079250 E.C.J., 1113577). Fellowships (1058344 W.S.A, 1142669 J.M.H, 1172929 J.M.M and 1107149 J.S), an Independent Research Institutes Infrastructure Support Scheme Grant (9000587), and a Victorian State Government Operational Infrastructure Support Grant. E.C.J. is the recipient of a fellowship from the Lorenzo and Pamela Galli Charitable Trust.