IndraLab

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"Given that RIPK3 critically regulates necroptosis and that OTUB2 increases RIPK3 abundance and activity, we then assessed whether OTUB2 enhanced neuronal necroptosis via regulating RIPK3."
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"Besides, OTUB2 deficiency significantly reduced the levels of phosphorylated RIPK3 and MLKL in primary neurons after OGD (Fig. 6C–F), showing that OTUB2 increases neuronal necroptosis after ischemia."
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"Next, we specifically induced necroptosis with a cocktail of TNF-α, CHX, and Z-VAD-FMK (TCZ) and found that Otub2 cells died significantly less than Otub2 cells (Fig. 6G; Appendix Fig. S11D), unambiguously demonstrating that OTUB2 deletion diminishes necroptosis."
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"Treatment with the RIPK3 inhibitor GSK-872 or the MLKL inhibitor GW806742X restored the viability of Otub2 cells and erased the difference between the two genotypes after TCZ stimulation (Fig. 6G; Appendix Fig. S11E), indicating that OTUB2 promotes necroptosis by regulating the RIPK3-MLKL signaling."
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"Moreover, overexpression of OTUB2 increased necroptosis whereas overexpression of the OTUB2 C51S mutant exerted no effect (Fig. 6H)."
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"Collectively, these findings show that OTUB2 enhances ischemia-induced neuronal necroptosis by regulating RIPK3 through its DUB activity."
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"OTUB2 potentiates neuronal necroptosis after ischemia."
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"These in vitro and in vivo data synergistically demonstrate that OTUB2 enhances ischemic stroke injury by potentiating neuronal necroptosis through RIPK3.Since OTUB2 promoted neuronal necroptosis and genetic deletion of OTUB2 ameliorated ischemic stroke injury, we further investigated whether inhibition of OTUB2 with inhibitors could protect mice from ischemic stroke."
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"In good agreement with the Western blot results, MLKL phosphorylation was significantly reduced in neurons of Otub2 mice after MCAO (Fig. 3H,I), showing that OTUB2 deficiency attenuates neuronal necroptosis."
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"To directly confirm that OTUB2 enhances neuronal necroptosis after the ischemic insult, Otub2 and Otub2 HT22 cells were subjected to oxygen-glucose deprivation (OGD)."
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"OTUB2 enhances neuronal necroptosis through RIPK3."
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