C6orf106 is a novel inhibitor of the interferon-regulatory factor 3–dependent innate antiviral response

Rebecca L Ambrose,Yu Chih Liu,Timothy E Adams,Andrew G.D Bean,Cameron R Stewart

doi:10.1074/jbc.ra117.001491

Abstract

Host recognition of intracellular viral RNA and subsequent induction of cytokine signaling are tightly regulated at the cellular level and are a target for manipulation by viruses and therapeutics alike. Here, we characterize chromosome 6 ORF 106 (C6orf106) as an evolutionarily conserved inhibitor of the innate antiviral response. C6orf106 suppresses the synthesis of interferon (IFN)-α/β and proinflammatory tumor necrosis factor (TNF) α in response to the dsRNA mimic poly(I:C) and to Sendai virus infection. Unlike canonical inhibitors of antiviral signaling, C6orf106 blocks interferon-regulatory factor 3 (IRF3) and, to a lesser extent, NF-κB activity without modulating their activation, nuclear translocation, cellular expression, or degradation. Instead, C6orf106 interacts with IRF3 and inhibits IRF3 recruitment to type I IFN promoter sequences while also reducing the nuclear levels of the coactivator proteins p300 and CREB-binding protein (CBP). In summary, we have defined C6orf106 as a negative regulator of antiviral immunity that blocks IRF3-dependent cytokine production via a noncanonical and poorly defined mechanism. This work presents intriguing implications for antiviral immunity, autoimmune disorders, and cancer.

Highlights

Host recognition of intracellular viral RNA and subsequent induction of cytokine signaling are tightly regulated at the cellular level and are a target for manipulation by viruses and therapeutics alike
C6orf106 interacts with interferon-regulatory factor 3 (IRF3) and inhibits IRF3 recruitment to type I IFN promoter sequences while reducing the nuclear levels of the coactivator proteins p300 and CREB-binding protein (CBP)
We show that C6orf106 does not interfere with cytoplasmic effectors and the activation/nuclear translocation of IRF3 or NF-␬B (Fig. 4) nor does it promote degradation of these transcription factors in the nucleus (Fig. 5)

Summary

ARTICLE cro

Unlike canonical inhibitors of antiviral signaling, C6orf106 blocks interferon-regulatory factor 3 (IRF3) and, to a lesser extent, NF-␬B activity without modulating their activation, nuclear translocation, cellular expression, or degradation. Activation of TRIF or MAVS promotes recruitment of multiple cytosolic effectors, resulting in the phosphorylation and dimerization of interferon-regulatory factor (IRF) 3 or liberation of NF-␬B from its inhibitory complex, respectively. These transcription factors are imported into the nucleus with activating transcription factor 2 (ATF2) and c-Jun and bind to the promoter region of the IFNB gene along with resident transcription factor high mobility group I(Y) [12]. We demonstrate that C6orf106 is an evolutionarily conserved inhibitor of IRF3-dependent antiviral cytokine production that targets IRF3 activity in the nucleus

Results

Discussion

Experimental procedures

Sendai virus infections

Transfections and drug treatments

Western blotting