Phosphorylation-Driven Assembly of RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation

By Youngsik Cho, Sreerupa Challa, D. Moquin, Ryan M. J. Genga, T. D. Ray, Melissa J. Guildford, F. Chan. Cell, 2009

2,353 citations recorded by the source corpus.

Programmed necrosis is a form of caspase-independent cell death whose molecular regulation is poorly understood. The protein kinase RIP1 is crucial for programmed necrosis. Because RIP1 also mediates activation of the pro-survival transcription factor NF-κB, we postulated that additional molecules are required to specifically activate programmed necrosis. Using a RNA interference screen, we identified RIP3 as a crucial activator for programmed necrosis induced by TNF and during virus infection. RIP3 regulates necrosis-specific RIP1 phosphorylation. The phosphorylation of RIP1 and RIP3 stabilizes their association within the pro-necrotic complex, activates the pro-necrotic kinase activity, and triggers downstream reactive oxygen species production. The pro-necrotic RIP1-RIP3 complex is induced during vaccinia virus infection. Consequently, RIP3−/− mice exhibited severely impaired virus-induced tissue necrosis, inflammation, and control of viral replication. Thus, RIP3 controls programmed necrosis by initiating the pro-necrotic kinase cascade that is essential for the innate inflammatory response against virus infections.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d5cf2e2f12e47bcd563c9fe24782521f164a3b2f

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Citations in the corpus

Pattern Recognition Receptors and the Host Cell Death Molecular Machinery (2018, background): “Mice lacking RIPK3 are highly sensitive to vaccinia virus due to widespread infection (120).”
Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis (2011, positive): “Necroptosis has been shown to be mediated by the kinases RIP1 and RIP3 15,16 .”
Apoptosis, autophagy, necroptosis, and cancer metastasis (2015, background): “During the progression of necroptosis, ROS are generated [125,126], resulting in lipid peroxidation and increased mitochondrial membrane permeability.”
The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics (2021, background): “Complex IIc activates the mixed lineage kinase domain-like protein (MLKL) via RIPK3-mediated phosphorylation, which induces necroptosis and inflammation (Figure 1) [13,20].”
Necroptosis: a regulated inflammatory mode of cell death (2018, background): “Experimental studies carried out on mice lacking RIPK3 exhibit impaired virus-induced necroptosis and increased sensitivity to viral infection [8, 13, 77, 79, 80].”
Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 (2011, background): “citotoxins and the ligation of death receptors, at least under selected circumstances.(9,11,12,84,85) Indeed, when caspases (and in particular caspase-8) are inhibited by genetic”
Programmed cell death in the plant immune system (2011, background): “During apoptosis, active caspase-8 can cleave RIP1 and RIP3 and abolish their kinase activity, preventing them from initiating necroptosis.(43) When apoptosis is blocked, necroptosis becomes the predominant form of cell death.”
MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. (2014, background): “When caspase-8 activation is compromised, apoptosis is inhibited, and the enzymatic activity of RIPK1 alternatively regulates the formation of the necrosome, a necroptosis-inducing complex consisting of RIPK1, RIPK3 (Cho et al., 2009; He et al., 2009; Zhang et al., 2009), and mixed lineage kinase do”
The role of necroptosis in cancer biology and therapy (2019, background): “Indeed, RIPK3 has been demonstrated to regulate the production of downstream ROS [101, 102] and could activate multiple metabolic en-”
Signaling in innate immunity and inflammation. (2012, background): “This death is dependent on the kinase activity of RIP1 and the related kinase RIP3 (Cho et al. 2009; He et al. 2009; Zhang et al. 2009).”