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CNOT3 supports ILC2 differentiation and function by destabilizing Tbx21 and Rorc transcripts

Megumi Tatematsu1, Shunsuke Takasuga1, Akane Fuchimukai1

  • 1Department of Microbiology and Immunology, Akita University Graduate School of Medicine, Akita, Japan.

The Journal of Experimental Medicine
|May 12, 2026
PubMed

Insights

The CCR4-NOT complex subunit CNOT3 is crucial for innate lymphoid cell 2 (ILC2) function. Loss of CNOT3 dysregulates ILC2s, impairing immune responses and promoting type 1 and 3 gene expression.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Innate lymphoid cells (ILCs) are critical immune cells with distinct subtypes (ILC1, ILC2, ILC3) defined by transcription factors.
  • Posttranscriptional regulation, particularly mRNA decay mediated by the CCR4-NOT complex, is vital for ILC function but remains poorly understood.
  • CNOT3 is an essential subunit of the CCR4-NOT complex involved in mRNA deadenylation.

Purpose of the Study:

  • To investigate the impact of mRNA decay on ILC differentiation and function.
  • To determine the role of CNOT3 in the regulation of ILC2 cells.
  • To elucidate the molecular mechanisms by which CNOT3 controls ILC2 transcriptional programs.

Main Methods:

  • Conditional deletion of the Cnot3 gene in ILC2 cells.
  • Analysis of gene expression, including transcription factors (T-bet, GATA-3, RORγt) and signature genes.
  • Investigation of molecular interactions between CNOT3, Roquin, ZFP36L1, and target mRNAs (Tbx21, Rorc).
  • Assessment of ILC2 function in models of airway allergy and helminth infection.

Main Results:

  • Loss of CNOT3 in ILC2 cells resulted in aberrant expression of T-bet and RORγt.
  • CNOT3 deficiency led to the upregulation of type 1 and type 3 signature genes in ILC2s.
  • CNOT3 directly targeted Tbx21 and Rorc mRNAs via Roquin and ZFP36L1, respectively.
  • Elevated T-bet suppressed GATA-3, impairing type 2 immune responses in vivo.
  • CNOT3 deficiency compromised ILC2 function in airway allergy and helminth infection models.

Conclusions:

  • CNOT3 is essential for maintaining ILC2 cell identity and function.
  • CNOT3 restricts the expression of type 1 (T-bet) and type 3 (RORγt) transcriptional programs in ILC2s.
  • This study reveals a critical role for mRNA decay in regulating ILC subset balance and immune homeostasis.

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