DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRA

Upton, Jason W.; Kaiser, William J.; Mocarski, Edward S.

doi:10.1016/j.chom.2012.01.016

Cited by 611 publications

(592 citation statements)

References 43 publications

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“…Thus, viruses can trigger necroptosis, and RIP3-deficient mice are more susceptible to infection by a number of pathogenic viruses including herpes simplex virus 1 55 and murine cytomegalovirus, 56 supporting the idea that necroptosis can restrain viral infection. In accord with this speculation, there is ample evidence that pathogenic viruses can manipulate RIP3-dependent necroptosis, 57,58 perhaps as a strategy for immune escape.…”

Section: Discussionmentioning

confidence: 83%

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Yang¹,

Ma²,

Guo³

et al. 2016

OncoImmunology

145

129

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Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo. Chemotherapy normally killed Rip3 ¡/¡ and Mlkl ¡/¡ tumor cells and normally induced caspase-3 activation in such cells, yet was unable to reduce their growth in vivo. RIP3 or MLKL deficiency abolished the capacity of dying cancer cells to elicit an immune response. This could be attributed to reduced release of ATP and high mobility group box 1 (HMGB1) by RIP3 and MLKL-deficient cells. Measures designed to compensate for deficient ATP and HMGB1 signaling restored the chemotherapeutic response of Rip3 ¡/¡ and Mlkl ¡/¡ cancers. Altogether, these results suggest that RIP3 and MLKL can contribute to ICD signaling and tumor immunogenicity.

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Section: Discussionmentioning

confidence: 83%

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Yang¹,

Ma²,

Guo³

et al. 2016

OncoImmunology

145

129

View full text Add to dashboard Cite

show abstract

“…Inhibitors of PGAM5 might therefore prevent execution of necroptosis. (iii) DNA-dependent activator of IRF is thought to act as a DNA sensor that induces interferon-1 production and interacts with RIP3 during viral infectioninduced necroptotic cell death, 43 so would most likely be beneficial for retinal degeneration associated with an immune response. (iv) Most recently, SIRT2 has been shown to regulate the deacetylation of RIP1, which is required for stable RIP1-RIP3 complex formation through RIP homotypic interaction motifs, and this deacetylation is RIP3-dependent process.…”

Section: Discussionmentioning

confidence: 99%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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“…The interaction of DAI with RIP3 also sensitizes cells to murine cytomegalovirus (MCMV)-induced necrosis with DAI-and RIP3-deficient cells being resistant to this form of death. 115 Intriguingly, MCMV encodes a M45 protein, that also contains a RHIM and targets the DAI-RIP3 interaction to suppress premature killing of endothelial cells during MCMV infection. 116,117 Such findings highlight the importance of RIPmediated necroptosis to anti-viral immunity.…”

Section: Rip Kinases and Nucleic Acid Sensingmentioning

confidence: 99%