Abstract
Innate immunity to nucleic acids forms the backbone for anti-viral immunity and several inflammatory diseases. Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type I interferon (IFN-I). TRAF3-interacting protein 3 (TRAF3IP3, T3JAM) is essential for T and B cell development. It is also well-expressed by myeloid cells, where its role is unknown. Here we report that TRAF3IP3 suppresses cytosolic poly(I:C), 5’ppp-dsRNA, and vesicular stomatitis virus (VSV) triggers IFN-I expression in overexpression systems and Traf3ip3−/− primary myeloid cells. The mechanism of action is through the interaction of TRAF3IP3 with endogenous TRAF3 and TBK1. This leads to the degradative K48 ubiquitination of TBK1 via its K372 residue in a DTX4-dependent fashion. Mice with myeloid-specific gene deletion of Traf3ip3 have increased RNA virus-triggered IFN-I production and reduced susceptibility to virus. These results identify a function of TRAF3IP3 in the regulation of the host response to cytosolic viral RNA in myeloid cells.
Highlights
Innate immunity is the first line of host defense against microbial infection and is evolutionally conserved in all multicellular organisms across Linnaean borders[1,2]
To explore the function of TRAF3IP3 in innate immunity, we investigated whether TRAF3IP3 had a substantial impact on IFN-I signaling
Overexpression of TRAF3IP3 suppressed IRF3 phosphorylation induced by cytosolic poly(I:C), poly(dA:dT) and 5′ppp-dsRNA stimulation (Fig. 1i, j, densitometric measurements shown in Supplementary Fig. 2c, d), and inhibited IRF3 translocation into the nucleus induced by cytosolic poly(I:C) (Fig. 1k)
Summary
Innate immunity is the first line of host defense against microbial infection and is evolutionally conserved in all multicellular organisms across Linnaean borders[1,2]. In HEK293T cells, cytosolic poly(I:C), poly(dA:dT), 5′ppp-dsRNA stimulation or vesicular stomatitis virus (VSV) infection activated IFN-β and ISRE promotor-driven luciferase reporters were all reduced by TRAF3IP3 in a dosedependent fashion (Fig. 1a–h).
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