Journal article
HSP90 activity is required for MLKL oligomerisation and membrane translocation and the induction of necroptotic cell death
AV Jacobsen, KN Lowes, MC Tanzer, IS Lucet, JM Hildebrand, EJ Petrie, MF Van Delft, Z Liu, SA Conos, JG Zhang, DCS Huang, J Silke, G Lessene, JM Murphy
Cell Death and Disease | NATURE PUBLISHING GROUP | Published : 2016
Abstract
Necroptosis is a caspase-independent form of regulated cell death that has been implicated in the development of a range of inflammatory, autoimmune and neurodegenerative diseases. The pseudokinase, Mixed Lineage Kinase Domain-Like (MLKL), is the most terminal known obligatory effector in the necroptosis pathway, and is activated following phosphorylation by Receptor Interacting Protein Kinase-3 (RIPK3). Activated MLKL translocates to membranes, leading to membrane destabilisation and subsequent cell death. However, the molecular interactions governing the processes downstream of RIPK3 activation remain poorly defined. Using a phenotypic screen, we identified seven heat-shock protein 90 (HSP..
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Awarded by James Merrill House
Funding Acknowledgements
We thank Dr Vishva Dixit for kindly providing Ripk3<SUP>-/-</SUP> mice, Dr Toru Okamoto for developing the inducible expression vector, Drs Marie-Liesse Asselin-Labat and Chris Burns for providing AT13387, and Mr Sam Young for assistance in generating expression constructs. This work was supported by National Health and Medical Research Council of Australia (NHMRC) grants (1067289, 1016647, 1057888, 1057905, 1046010 and 1016701) and fellowships to MFvD (516795), JMH (541951), DCSH (1043149) and JS (541901, 1058190); a Victorian International Research Scholarship to MCT; with additional support from the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support Scheme and an NHMRC IRIISS grant (9000220). This research was facilitated by Compounds Australia; a joint initiative of Griffith University and the Queensland Government through the Smart State Innovation Fund administered by the Department of Tourism, Regional Development and Industry.