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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
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Pyrimidine synthesis enzyme CTP synthetase 1 suppresses antiviral interferon induction by deamidating IRF3

Youliang Rao1, Chao Qin1, Ali Can Savas1

  • 1Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.

Immunity
|December 25, 2024
PubMed

Insights

Metabolic enzyme CTPS1 negatively regulates innate immunity by deamidating IRF3, which dampens interferon production. Immune activation inhibits this process, allowing for robust interferon induction.

Area of Science:

  • Immunology
  • Metabolic Biochemistry

Background:

  • Metabolic enzymes are primarily studied for their roles in growth and proliferation.
  • The functions of metabolic enzymes in regulating innate immune responses are largely unexplored.

Purpose of the Study:

  • To investigate the non-metabolic roles of metabolic enzymes in innate immunity.
  • To identify novel regulators of interferon induction pathways.

Main Methods:

  • Conducted a short hairpin RNA (shRNA)-mediated screen to identify regulators of interferon induction.
  • Utilized CTPS1 conditional deletion and IRF3 knockin mouse models.
  • Investigated the interaction and enzymatic activity of CTPS1 on IRF3.

Main Results:

  • Identified CTPS1, a pyrimidine synthesis enzyme, as a negative regulator of interferon induction.
  • CTPS1 deamidates IRF3 at N85, impairing its DNA binding and subsequent interferon (IFN) induction.
  • CTPS1-mediated IRF3 deamidation restricts IFN induction during viral infection in vivo.
  • GSK3β inhibits CTPS1-mediated IRF3 deamidation during immune activation, promoting IFN induction.

Conclusions:

  • CTPS1 regulates innate immunity independently of its metabolic function.
  • CTPS1's role in IRF3 deamidation highlights a novel mechanism for controlling interferon responses.
  • This study expands the known functions of metabolic enzymes into the realm of immune regulation.
Keywords:
CTP synthetaseRNA and DNA virusesinterferon productioninterferon regulatory factorprotein deamidationpyrimidine synthesis enzyme

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