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A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling.

Kislay Parvatiyar | Jose Pindado | Anurupa Dev | Saba Roghiyh Aliyari | Shivam A Zaver | Hoda Gerami | Maxime Chapon | Amir A Ghaffari | Anant Dhingra | Genhong Cheng
Nature communications | 2018

Detection of viral genomes by the innate immune system elicits an antiviral gene program mediated by type I interferons (IFNs). While viral RNA and DNA species induce IFN via separate pathways, the mechanisms by which these pathways are differentially modulated are unknown. Here we show that the positive regulator of IFN in the RNA pathway, TRAF3, has an inhibitory function in the DNA pathway. Loss of TRAF3 coincides with increased expression of the alternative NF-κB-inducing molecule, NIK, which interacts with the DNA pathway adaptor, STING, to enhance IFN induction. Cells lacking NIK display defective IFN activation in the DNA pathway due to impaired STING signaling, and NIK-deficient mice are more susceptible to DNA virus infection. Mechanistically, NIK operates independently from alternative NF-κB signaling components and instead requires autophosphorylation and oligomerization to activate STING. Thus a previously undescribed pathway for NIK exists in activating IFN in the DNA pathway.

Pubmed ID: 30018345

Associated grants

  • Agency: NIAID NIH HHS, United States
    Id: R01 AI069120
  • Agency: NCI NIH HHS, United States
    Id: T32 CA009056
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI056154
  • Agency: NIAID NIH HHS, United States
    Id: T32 AI060567
  • Agency: NIAID NIH HHS, United States
    Id: R56 AI078389
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI078389

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