Journal ArticleDOI
Necroptosis signalling is tuned by phosphorylation of MLKL residues outside the pseudokinase domain activation loop
Maria C. Tanzer,Maria C. Tanzer,Anne Tripaydonis,Anne Tripaydonis,Andrew I. Webb,Andrew I. Webb,Samuel N. Young,Leila N. Varghese,Leila N. Varghese,Cathrine Hall,Warren S. Alexander,Warren S. Alexander,Joanne M Hildebrand,Joanne M Hildebrand,John Silke,John Silke,James M. Murphy,James M. Murphy +17 more
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TLDR
Exercise of a phosphomimetic S345D MLKL activation loop mutant-induced stimulus-independent cell death in all knockout cells is demonstrated, demonstrating that RIPK3 phosphorylation of the activation loop ofMLKL is sufficient to induce cell death.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) and Ser(248). Expression of a phosphomimetic S345D MLKL activation loop mutant-induced stimulus-independent cell death in all knockout cells, demonstrating that RIPK3 phosphorylation of the activation loop of MLKL is sufficient to induce cell death. Cell death was also induced by S228A, S228E and S158A MLKL mutants in the absence of death stimuli, but was most profound in Mlkl(-/-)Ripk3(-/-) double knockout fibroblasts. These data reveal a potential role for RIPK3 as a suppressor of MLKL activation and indicate that phosphorylation can fine-tune the ability of MLKL to induce necroptosis.read more
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Journal ArticleDOI
Programmed cell death as a defence against infection.
TL;DR: The role of different cell death pathways in innate immune defence against bacterial and viral infection is discussed: apoptosis, necroptosis, pyroptosis and NETosis, which create complex signalling networks that cross-guard each other in the evolutionary 'arms race' with pathogens.
Journal ArticleDOI
Necroptosis: Mechanisms and Relevance to Disease
TL;DR: Accumulating evidence indicates that necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance.
Journal ArticleDOI
Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure.
Tammo Müller,Christin Dewitz,Jessica Schmitz,Anna Sophia Schröder,Jan Hinrich Bräsen,Brent R. Stockwell,James M. Murphy,Ulrich Kunzendorf,Stefan Krautwald +8 more
TL;DR: Findings reveal ACSL4 to be a reliable biomarker of the emerging cell death modality of ferroptosis, which may also serve as a novel therapeutic target in preventing pathological cell death processes.
Journal ArticleDOI
A major role for ferroptosis in Mycobacterium tuberculosis -induced cell death and tissue necrosis.
Eduardo P. Amaral,Diego L. Costa,Sivaranjani Namasivayam,Nicolas Riteau,Nicolas Riteau,Olena Kamenyeva,Lara R. Mittereder,Katrin D. Mayer-Barber,Bruno B. Andrade,Alan Sher +9 more
TL;DR: Findings implicate ferroptosis as a major mechanism of necrosis in Mtb infection and as a target for host-directed therapy of tuberculosis.
Journal ArticleDOI
MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis
Andre L. Samson,Andre L. Samson,Ying Zhang,Ying Zhang,Niall D. Geoghegan,Niall D. Geoghegan,Xavier J Gavin,Katherine A Davies,Katherine A Davies,Michael J. Mlodzianoski,Michael J. Mlodzianoski,Lachlan Whitehead,Lachlan Whitehead,Daniel Frank,Daniel Frank,Sarah E Garnish,Sarah E Garnish,Cheree Fitzgibbon,Anne Hempel,Samuel N. Young,Annette V. Jacobsen,Annette V. Jacobsen,Wayne Cawthorne,Wayne Cawthorne,Emma J. Petrie,Emma J. Petrie,Maree C. Faux,Maree C. Faux,Kristy Shield-Artin,Kristy Shield-Artin,Najoua Lalaoui,Najoua Lalaoui,Joanne M Hildebrand,Joanne M Hildebrand,John Silke,John Silke,Kelly L. Rogers,Kelly L. Rogers,Guillaume Lessene,Guillaume Lessene,Edwin D. Hawkins,Edwin D. Hawkins,James M. Murphy,James M. Murphy +43 more
TL;DR: It is shown that MLKL trafficking and plasma membrane accumulation are crucial necroptosis checkpoints, and that accumulation of phosphorylatedMLKL at intercellular junctions promotes necroPTosis.
References
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Anne M. Verhagen,Paul G Ekert,Paul G Ekert,Miha Pakusch,John Silke,Lisa M. Connolly,Gavin E. Reid,Robert L. Moritz,Richard J. Simpson,David L. Vaux +9 more
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Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation
Young Sik Cho,Sreerupa Challa,David Moquin,Ryan M.J. Genga,Tathagat Dutta Ray,Melissa J. Guildford,Francis Ka-Ming Chan +6 more
TL;DR: The findings suggest that RIP3 controls programmed necrosis by initiating the pronecrotic kinase cascade, and that this is necessary for the inflammatory response against virus infections.
Journal ArticleDOI
Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase
Liming Sun,Huayi Wang,Zhigao Wang,Sudan He,She Chen,Daohong Liao,Lai Wang,Jiacong Yan,Weilong Liu,Xiaoguang Lei,Xiaodong Wang +10 more
TL;DR: The identification of a small molecule called necrosulfonamide that specifically blocks necrosis downstream of RIP3 activation is reported, which implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3.
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