Annette V. Jacobsen

A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease

Jiyi Pang, Aysha Al‐Ani, Komal M. Patel, Yunzhuo Zhou et autres

Inflammatory bowel disease (IBD) is a chronic condition caused by altered cytokine signaling, maladaptive immunity, dysbiosis, and intestinal barrier dysfunction. Although current therapies aim to correct these imbalances to induce remission, most patients ultimately relapse, suggesting that key pathogenic mechanisms persist. Here, …

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Su1887: CELL DEATH DYSREGULATION IS A MOLECULAR HALLMARK OF INFLAMMATORY BOWEL DISEASE (IBD)

Aysha Al‐Ani, Jiyi Pang, Komal M. Patel, Sam Young et autres

Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation

Sarah E. Garnish, Christopher R. Horne, Yanxiang Meng, Samuel N. Young et autres

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 trafficked to the plasma membrane via the Golgi-, actin- and …

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An immunohistochemical atlas of necroptotic pathway expression

Shene Chiou, Aysha Al‐Ani, Yi Pan, Komal M. Patel et autres

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 cells and tissues that undergo …

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An immunohistochemical atlas of necroptotic pathway expression

Shene Chiou, Aysha Al‐Ani, Yi Pan, Komal M. Patel et autres

Abstract 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 cells and tissues that …

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A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation

Sarah E. Garnish, Katherine Martin, Maria Kauppi, Victoria E. Jackson et autres

Abstract 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. Here we show that this substitution confers a gain in necroptotic function in human …

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The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase

Catia L. Pierotti, Annette V. Jacobsen, Christoph Grohmann, Ruby K. Dempsey et autres

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 and RIPK3. Dysregulated necroptosis has been implicated in the pathophysiology of …

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A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation

Sarah E. Garnish, Katherine Martin, Maria Kauppi, Victoria E. Jackson et autres

ABSTRACT 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 necroptotic function in human …

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Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms

Christoph Grohmann, Charlene M. Magtoto, Joel R. Walker, Ngee Kiat Chua et autres

Abstract Modulation of protein abundance using t ag- T argeted P rotein D egrader (tTPD) systems targeting FKBP12 F36V (dTAGs) or HaloTag7 (HaloPROTACs) are powerful approaches for preclinical target validation. Interchanging tags and tag-targeting degraders is important to achieve efficient substrate degradation, …

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The Lck inhibitor, AMG-47a, blocks necroptosis and implicates RIPK1 in signalling downstream of MLKL

Annette V. Jacobsen, Catia L. Pierotti, Kym N. Lowes, Amanda E. Au et autres

Necroptosis is a form of caspase-independent programmed cell death that arises from disruption of cell membranes by the mixed lineage kinase domain-like (MLKL) pseudokinase after its activation by the upstream kinases, receptor interacting protein kinase (RIPK)-1 and RIPK3, within a complex known …

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Membrane permeabilization is mediated by distinct epitopes in mouse and human orthologs of the necroptosis effector, MLKL

Ashish Sethi, Christopher R. Horne, Cheree Fitzgibbon, Karyn L. Wilde et autres

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CRISPR deletions in cell lines for reconstitution studies of pseudokinase function

Annette V. Jacobsen, James M. Murphy

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