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Your search keyword '"Alturki, Norah A."' showing total 3 results
Start Over Author "Alturki, Norah A." Topic apoptosis
3 results on '"Alturki, Norah A."'

1. Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Author

Alturki NA, McComb S, Ariana A, Rijal D, Korneluk RG, Sun SC, Alnemri E, and Sad S

Subjects
Animals, Inhibitor of Apoptosis Proteins metabolism, Lysine metabolism, Mice, Inbred C57BL, Necrosis, Proteasome Endopeptidase Complex metabolism, Protein Binding, Ubiquitination, Apoptosis, Cytokines biosynthesis, Proteolysis, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Ubiquitin-Protein Ligases metabolism
Abstract

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses.

Published
2018
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2. Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages.

Author

McComb S, Cessford E, Alturki NA, Joseph J, Shutinoski B, Startek JB, Gamero AM, Mossman KL, and Sad S

Subjects
Animals, Enzyme Activation drug effects, Inflammation, Lipopolysaccharides pharmacology, Macrophages drug effects, Mice, Mice, Inbred C57BL, Models, Biological, Necrosis, Oligopeptides pharmacology, Poly I-C pharmacology, Receptor, Interferon alpha-beta deficiency, Receptor, Interferon alpha-beta metabolism, Receptor-Interacting Protein Serine-Threonine Kinases deficiency, Tumor Necrosis Factor-alpha pharmacology, Apoptosis drug effects, Interferon Type I metabolism, Interferon-Stimulated Gene Factor 3, gamma Subunit metabolism, Macrophages metabolism, Macrophages pathology, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Signal Transduction drug effects
Abstract

Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. Recently the death of macrophages through programmed necrosis (necroptosis) has emerged as an important mechanism in inflammation and pathology. We evaluated the mechanisms that lead to the induction of necrotic cell death in macrophages. Our results indicate that type I IFN (IFN-I) signaling is a predominant mechanism of necroptosis, because macrophages deficient in IFN-α receptor type I (IFNAR1) are highly resistant to necroptosis after stimulation with LPS, polyinosinic-polycytidylic acid, TNF-α, or IFN-β in the presence of caspase inhibitors. IFN-I-induced necroptosis occurred through both mechanisms dependent on and independent of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and led to persistent phosphorylation of receptor-interacting protein 3 (Rip3) kinase, which resulted in potent necroptosis. Although various IFN-regulatory factors (IRFs) facilitated the induction of necroptosis in response to IFN-β, IRF-9-STAT1- or -STAT2-deficient macrophages were highly resistant to necroptosis. Our results indicate that IFN-β-induced necroptosis of macrophages proceeds through tonic IFN-stimulated gene factor 3 (ISGF3) signaling, which leads to persistent expression of STAT1, STAT2, and IRF9. Induction of IFNAR1/Rip3-dependent necroptosis also resulted in potent inflammatory pathology in vivo. These results reveal how IFN-I mediates acute inflammation through macrophage necroptosis.

Published
2014
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3. Necrosome Activation and Degradation in Macrophages

Author

Alturki, Norah Abdullah

Subjects
Degradation, type-I IFN, Necrosome, RipK1, Necroptosis, Apoptosis, RipK3, Toll like receptors, Programmed cell death, MLKL
Abstract

Necroptosis is a recently discovered form of cell death that is distinct from apoptosis that promotes inflammation. Necroptosis is induced upon engagement of various classical death receptors such as tumor necrotic factor receptor (TNFR) and Fas ligand, and also by engagement of toll like receptors involved in recognition of various pathogen associated molecular patterns such as lipopolysaccharide (LPS) and polyinosinic: polycytidylic acid (poly I:C). Necroptosis is induced by the activation of receptor-interacting protein kinase-1 (RipK1) and receptor-interacting protein kinase-3 (RipK3) that leads to phosphorylation-driven trimerization and consequent translocation of the mixed lineage kinase domain-like (MLKL) protein to the cell membrane, resulting in cell rupture. The formation of this necrosome complex is highly regulated by phosphorylation and ubiquitination. The precise mechanisms through which members of the necrosome assemble sequentially in macrophages are not clear. Herein I have evaluated the mechanisms that promote the assembly and degradation of the necrosome in macrophages. In the first aim of my thesis I revealed that during early necrosome formation RipK3 destabilizes the complex by promoting degradation of interacting proteins. RipK3 promoted K48-ubiquitin dependent proteasomal degradation of various necrosome interacting proteins such as RipK1, CASPASE-8, and FADD. This degradation event occurred independently of other ubiquitin editing enzymes such as cIAP1/2, A20 and CYLD that are known to edit RipK1. I further show that this degradation of early necrosomal proteins is mediated by the E3-ubiquiting ligase Triad3a (RNF216). Knocking-down Triad3a prevented degradation of necrosome proteins, enhanced necroptosis and production of inflammatory cytokines. In the second section of my thesis, I evaluated the mechanisms responsible for necrosome signalling following engagement of type-I interferon receptor. I show that the downstream Janus kinase (JAKs) kinases (TYK2 and JAK1) are required for necroptosis in macrophages. My results indicate that IFNAR1 signalling promotes phosphorylation of RipK3 and MLKL, the two events that are required for necroptosis. Furthermore, I observed that type-I interferon signalling promotes the transcription of MLKL and the phosphorylation driven oligomerization of MLKL which is necessary for pore formation in cells. Finally, inhibition of the p38MAPK pathway abrogated the resistance of Ifnar1-/- macrophages. The results presented in this thesis reveal mechanisms that regulate necrosome signalling and will help identify potential therapeutic targets that could be exploited in chronic inflammatory conditions.

Published
2020
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