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 and Genhong Cheng ()
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Kislay Parvatiyar: UCLA
Jose Pindado: UCLA
Anurupa Dev: University of California, Los Angeles (UCLA)
Saba Roghiyh Aliyari: UCLA
Shivam A. Zaver: UCLA
Hoda Gerami: UCLA
Maxime Chapon: UCLA
Amir A. Ghaffari: UCLA
Anant Dhingra: UCLA
Genhong Cheng: UCLA

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05168-7

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