Joanne M. Hildebrand
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View article: Lipid nanoparticle-delivered intrabodies for inhibiting necroptosis and pyroptosis
Lipid nanoparticle-delivered intrabodies for inhibiting necroptosis and pyroptosis Open
Intrabodies are intracellularly expressed high-affinity protein binders such as nanobodies and monobodies that offer an alternative approach to small molecules. However, the maturation of intrabody technology into new therapeutic modalitie…
View article: Lipid nanoparticle delivered intrabodies for inhibiting necroptosis and pyroptosis
Lipid nanoparticle delivered intrabodies for inhibiting necroptosis and pyroptosis Open
Intrabodies are intracellularly expressed high-affinity protein binders such as nanobodies and monobodies that offer an alternative approach to small molecules. However, the maturation of intrabody technology into new therapeutic modalitie…
View article: The kinase domain of RIPK3 tunes its scaffolding functions
The kinase domain of RIPK3 tunes its scaffolding functions Open
The pro-inflammatory programmed cell death pathway, necroptosis, relies on phosphorylation of the terminal effector, MLKL, by RIPK3. RIPK3-deficient mice or those harboring the kinase-inactivating mutation, RIPK3 K51A , are ostensibly norm…
View article: Divergent roles of RIPK3 and MLKL in high-fat diet–induced obesity and MAFLD in mice
Divergent roles of RIPK3 and MLKL in high-fat diet–induced obesity and MAFLD in mice Open
Cell death frequently occurs in the pathogenesis of obesity and metabolic dysfunction–associated fatty liver disease (MAFLD). However, the exact contribution of core cell death machinery to disease manifestations remains ill-defined. Here,…
View article: Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation
Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation Open
Necroptosis is a lytic and pro-inflammatory form of programmed cell death executed by the terminal effector, the MLKL (mixed lineage kinase domain-like) pseudokinase. Downstream of death and Toll-like receptor stimulation, MLKL is traffick…
View article: Defining a Water-Soluble Formulation of Arachidonic Acid as a Novel Ferroptosis Inducer in Cancer Cells
Defining a Water-Soluble Formulation of Arachidonic Acid as a Novel Ferroptosis Inducer in Cancer Cells Open
Here, we describe GS-9, a novel water-soluble fatty acid-based formulation comprising L-lysine and arachidonic acid, that we have shown to induce ferroptosis. GS-9 forms vesicle-like structures in solution and mediates lipid peroxidation, …
View article: An immunohistochemical atlas of necroptotic pathway expression
An immunohistochemical atlas of necroptotic pathway expression Open
Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the …
View article: MLKL variant call files
MLKL variant call files Open
Variant call files for MLKL p.Ser132Pro polymorphism carrier
View article: The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase
The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase Open
Necroptosis is a mode of programmed, lytic cell death that is executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following activation by the upstream kinases, receptor-interacting serine/threonine protein kinase (RIPK)-1 …
View article: Divergent roles for caspase-8 and MLKL in high-fat diet induced obesity and NAFLD in mice
Divergent roles for caspase-8 and MLKL in high-fat diet induced obesity and NAFLD in mice Open
Cell death frequently occurs in the pathogenesis of obesity and non-alcoholic fatty liver disease (NAFLD). However, the exact contribution of core cell death machinery to disease manifestations remains ill-defined. Here, we show via the di…
View article: MLKL deficiency protects against low-grade, sterile inflammation in aged mice
MLKL deficiency protects against low-grade, sterile inflammation in aged mice Open
MLKL and RIPK3 are the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every phys…
View article: A common human<i>MLKL</i>polymorphism confers resistance to negative regulation by phosphorylation
A common human<i>MLKL</i>polymorphism confers resistance to negative regulation by phosphorylation Open
Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL , the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. We show that this substitution confers a gain in …
View article: Add necroptosis to your asthma action plan
Add necroptosis to your asthma action plan Open
Necroptosis is one of several programmed lytic cell death processes for which key effector proteins have only been defined and experimentally dissected in the last decade. Unlike apoptotic cell death, where cellular contents undergo membra…
View article: The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease
The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease Open
Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain und…
View article: The Role of the Key Effector of Necroptotic Cell Death, Mlkl, in Mouse Models of Disease
The Role of the Key Effector of Necroptotic Cell Death, Mlkl, in Mouse Models of Disease Open
Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein – MLKL – shows no overt phenotype in the C57BL/6 …
View article: Membrane permeabilization is mediated by distinct epitopes in mouse and human orthologs of the necroptosis effector, MLKL
Membrane permeabilization is mediated by distinct epitopes in mouse and human orthologs of the necroptosis effector, MLKL Open
Necroptosis is a lytic programmed cell death pathway with origins in innate immunity that is frequently dysregulated in inflammatory diseases. The terminal effector of the pathway, MLKL, is licensed to kill following phosphorylation of its…
View article: Oligomerization-driven MLKL ubiquitylation antagonises necroptosis
Oligomerization-driven MLKL ubiquitylation antagonises necroptosis Open
Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase-independent form of programmed cell death called necroptosis. Receptor Interacting serine/threonine Protein Kinase 3 (RIPK3) phosphorylates MLKL, triggering MLKL oli…
View article: A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes
A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes Open
Maturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX…
View article: A toolbox for imaging RIPK1, RIPK3 and MLKL in mouse and human cells
A toolbox for imaging RIPK1, RIPK3 and MLKL in mouse and human cells Open
Necroptosis is a lytic, inflammatory cell death pathway that is dysregulated in many human pathologies. The pathway is executed by a core machinery comprising the RIPK1 and RIPK3 kinases, which assemble into necrosomes in the cytoplasm, an…
View article: MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis
MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis Open
Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. RIPK3-mediated phosphorylation is thought to initiate MLKL oligomerization, membrane translocation and membrane disrupt…