LAUSR

Description ID2 reduces the interferon response to viral infections by inhibiting the activation of IRF3. ID2 interferes with IRF3 activation Inhibitor of DNA binding protein 2 (ID2) controls the development and differentiation of various immune cell types by inhibiting certain transcription factors in the nucleus. Yu et al. found a role for cytoplasmic ID2 in attenuating the production of type I interferons (IFNs) in virus-infected human epithelial cells and mice. In cells, viral infection resulted in the binding of ID2 to the cytoplasmic kinases TBK1 and IKKε, which reduced their ability to activate IFN regulatory factor 3 (IRF3), leading to a decrease in IRF3-dependent IFNB1 expression. Knocking out ID2 enhanced antiviral responses in human cells and made mice more resistant to infection from RNA and DNA viruses. The authors also identified a negative feedback loop in which IFN-β promoted the nuclear export of ID2. These findings delineate the mechanisms by which ID2 attenuates innate immune responses to viral infection. The transcription regulator ID2 plays an essential role in the development and differentiation of immune cells. Here, we report that ID2 also negatively regulates antiviral innate immune responses. During viral infection of human epithelial cells, ID2 bound to TANK-binding kinase 1 (TBK1) and to inhibitor of nuclear factor κB kinase ε (IKKε). These interactions inhibited the recruitment and activation of interferon (IFN) regulatory factor 3 (IRF3) by TBK1 or IKKε, leading to a reduction in the expression of IFN-β1 (IFNB1). IFN-β induced the nuclear export of ID2 to form a negative feedback loop. Knocking out ID2 in human cells enhanced innate immune responses and suppressed infection by different viruses, including SARS-CoV-2. Mice with a myeloid-specific deficiency of ID2 produced more IFN-α in response to viral infection and were more resistant to viral infection than wild-type mice. Our findings not only establish ID2 as a modulator of IRF3 activation induced by TBK1 and/or IKKε but also introduce a mechanism for cross-talk between innate immunity and cell development and differentiation.