CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins
Copyright policy )CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins
AbstractThe CCR4-NOT complex is conserved in eukaryotes and is involved in mRNA metabolism, though its molecular physiological roles remain to be established. We show here that CNOT3-depleted mouse embryonic fibroblasts (MEFs) undergo cell death. Levels of other complex subunits are decreased in CNOT3-depleted MEFs. The death phenotype is rescued by introduction of wild-type (WT), but not mutated CNOT3 and is not suppressed by the pan-caspase inhibitor, zVAD-fluoromethylketone. Gene expression profiling reveals that mRNAs encoding cell death-related proteins, including receptor-interacting protein kinase 1 (RIPK1) and RIPK3, are stabilized in CNOT3-depleted MEFs. Some of these mRNAs bind to CNOT3 and in the absence of CNOT3 their poly(A) tails are elongated. Inhibition of RIPK1-RIPK3 signaling by a short-hairpin RNA or a necroptosis inhibitor, necrostatin-1, confers viability upon CNOT3-depleted MEFs. Therefore, we conclude that CNOT3 targets specific mRNAs to prevent cells from being disposed to necroptotic death.
Indoles, Cell Death, Cell Survival, Leupeptins, RNA Stability, Primary Cell Culture, Imidazoles, Cysteine Proteinase Inhibitors, Fibroblasts, Embryo, Mammalian, Caspase Inhibitors, Article, Amino Acid Chloromethyl Ketones, Mice, Gene Expression Regulation, Receptor-Interacting Protein Serine-Threonine Kinases, Animals, RNA, Messenger, RNA, Small Interfering, Protein Binding, Signal Transduction
Indoles, Cell Death, Cell Survival, Leupeptins, RNA Stability, Primary Cell Culture, Imidazoles, Cysteine Proteinase Inhibitors, Fibroblasts, Embryo, Mammalian, Caspase Inhibitors, Article, Amino Acid Chloromethyl Ketones, Mice, Gene Expression Regulation, Receptor-Interacting Protein Serine-Threonine Kinases, Animals, RNA, Messenger, RNA, Small Interfering, Protein Binding, Signal Transduction
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