Journal article

Necroptosis signalling is tuned by phosphorylation of MLKL residues outside the pseudokinase domain activation loop

Maria C Tanzer, Anne Tripaydonis, Andrew I Webb, Samuel N Young, Leila N Varghese, Cathrine Hall, Warren S Alexander, Joanne M Hildebrand, John Silke, James M Murphy

BIOCHEMICAL JOURNAL | PORTLAND PRESS LTD | Published : 2015

Abstract

The pseudokinase MLKL (mixed lineage kinase domain-like), has recently emerged as a critical component of the necroptosis cell death pathway. Although it is clear that phosphorylation of the activation loop in the MLKL pseudokinase domain by the upstream protein kinase RIPK3 (receptor-interacting protein kinase-3), is crucial to trigger MLKL activation, it has remained unclear whether other phosphorylation events modulate MLKL function. By reconstituting Mlkl(-/-), Ripk3(-/-) and Mlkl(-/-)Ripk3(-/-) cells with MLKL phospho-site mutants, we compared the function of known MLKL phosphorylation sites in regulating necroptosis with three phospho-sites that we identified by MS, Ser(158), Ser(228) ..

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Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by Australian Research Council


Awarded by National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme


Funding Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia [grant numbers 1016647, 1057888, 1057905, 1046010 and 1058344 (to W.S.A.), 541951 (to J.M.H.), and 541901 and 1058190 (to J.S.)]; the Australian Research Council Future Fellowship [grant number FT100100100 (to J.M.M.)]; the Victorian International Research Scholarship (to M.C.T.); the Victorian State Government Operational Infrastructure Support; and the National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme [grant number 9000220].