UCLA

Cells are equipped with a comprehensive set of sensors that permits rapid detection of viral infection and initiation of an antiviral immune response through secretion of type I interferons (IFNs). This series of studies focuses on elucidating in molecular detail the mechanisms of type I IFN induction via the retinoic acid inducible gene (RIG-I)-like receptor (RLR) and DNA-sensor pathways. A clearer understanding of how viral nucleic acids are recognized at the molecular level should aid development of novel antiviral therapies.

We report the crystal structures of the TRAF domains of TRAF5 and of TRAF3 bound to a peptide from the TIM of Cardif. We identify two residues in TRAF3 that allow TRAF3 to bind to Cardif, and we show that mutation of these two residues in TRAF5 to the corresponding TRAF3 residues confers TRAF3-like antiviral activity on the mutated TRAF5 proteins. Our results provide a structural basis for the critical role of TRAF3 in activating RIG-I–mediated IFN production.

We also present data showing that Optineurin is a positive regulator of non-canonical NFκB. We propose that on stimulation of the non-canonical NFκB pathway, Optineurin is recruited to the TRAF-cIAP-NIK complex, wherein it acts to promote TRAF3 degradation and support NIK accumulation. In light of our lab’s data showing that TRAF3 functions to inhibit the cytosolic IFNβ response to DNA, we hypothesize that Optineurin should function to promote IFNβ induction in the cytosolic DNA pathway.

Finally, we present results from a screen for genes capable of activating the type I IFN antiviral response. We focused our studies on the kinase LATS1, which we propose functions to promote IFNβ activation in response to cytosolic RNA and DNA pathways. We show that LATS1 promotes IFNβ activation in response to both pIC and BDNA-transfection. Mechanistically, we show that LATS1 associates with the TBK1/IRF3 complex after activation of either cytosolic RNA or DNA pathways, and that LATS1 acts to promote phosphorylation of TBK1 and IRF3, thereby so enhancing downstream IFNβ induction. We propose that LATS1 could serve as a bridge between viral infection and Hippo signaling.