TRAF3IP3 negatively regulates type I interferon signaling by suppressing TBK1

Abstract

Abstract Type I interferon (IFN) signaling is important for antiviral and autoimmune response, and it is subjected to tight control, however molecular mechanisms to tune down these pathways is incompletely understood. Upon sensing cytosolic viral RNA, retinoic acid-induced gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA5) interact with mitochondrial antiviral signaling protein (MAVS) and activate TANK binding kinase 1 (TBK1) to induce IFNs. A golgi-associated factor, TRAF3-interacting protein 3 (TRAF3IP3), has been found to be crucial for thymocyte development and T regulatory cell functions. However its role in myeloid cells has not been explored. We find that the overexpression of TRAF3IP3 suppressed cytosolic poly(I:C), 5’ ppp-dsRNA, and vesicular stomatitis virus (VSV) triggered IFN production, whereas deficiency of Traf3ip3 potentiated viral RNA triggered IFN production. In support of the in vitro data, Traf3ip3-deficient mice were infected with VSV and found to exhibit enhanced susceptibility to VSV challenge. Mechanistically, TRAF3IP3 interacted with TBK1 and targeted TBK1 for ubiquitination and degradation. These results uncovered a previously unrecognized role of TRAF3IP3 in the regulation of RNA induced IFN pathway.