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CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins

Toru Suzuki1, Chisato Kikuguchi1, Sahil Sharma1

  • 1Cell Signal Unit, Okinawa Institute of Science and Technology, 1919-1 Onna-son, Okinawa 904-0495, Japan.

Scientific Reports
|October 7, 2015
PubMed

Insights

CNOT3 depletion in mouse cells triggers necroptotic cell death by stabilizing specific mRNAs. Restoring CNOT3 or inhibiting RIPK1-RIPK3 signaling prevents this cell death, revealing CNOT3

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The CCR4-NOT complex regulates mRNA metabolism, but its precise physiological functions are not fully understood.
  • CNOT3 is a subunit of the CCR4-NOT complex, crucial for its function in eukaryotes.

Purpose of the Study:

  • To investigate the physiological role of CNOT3 in mammalian cells.
  • To elucidate the molecular mechanisms underlying cell death observed upon CNOT3 depletion.

Main Methods:

  • Depletion of CNOT3 in mouse embryonic fibroblasts (MEFs) using RNA interference.
  • Analysis of cell viability, caspase-independent cell death pathways, and mRNA expression profiling.
  • Investigation of mRNA-protein interactions and polyadenylation status.

Main Results:

  • CNOT3 depletion in MEFs leads to cell death, independent of caspases.
  • Stabilization of mRNAs encoding cell death mediators like RIPK1 and RIPK3 was observed.
  • CNOT3 directly binds to specific mRNAs, and its absence results in poly(A) tail elongation.
  • Inhibition of RIPK1-RIPK3 signaling rescues CNOT3-depleted cells from death.

Conclusions:

  • CNOT3 plays a critical role in preventing necroptotic cell death.
  • CNOT3 regulates the stability of specific mRNAs involved in cell death pathways.
  • The CCR4-NOT complex, through CNOT3, acts as a key regulator of programmed cell death.

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