LAUSR

The innate immune response is vital for host defense and must be tightly controlled, but the mechanisms responsible for its negative regulation have not been fully understood. The cell growth-regulating nucleolar protein (LYAR) has been found to promote replication of multiple viruses in our previous study. Here, we report that LYAR acts as a negative regulator of the innate immune responses. We find that LYAR expression is induced by interferon-β (IFN-β) during virus infection. Further studies show that LYAR interacts with the phosphorylated IFN regulatory factor 3 (IRF3) to impede the DNA binding capacity of IRF3, thereby suppressing the transcription of IFN-β and the downstream IFN-stimulated genes (ISGs). In addition, LYAR inhibits nuclear factor-κB (NF-κB) mediated expression of proinflammatory cytokines. In summary, our study reveals the mechanism of LYAR modulating IFN-β mediated innate immune responses by targeting phosphorylated IRF3, which not only helps us to better understand the mechanisms of LYAR-regulated virus replication but also uncovers a novel role of LYAR in the host innate immunity.IMPORTANCE IFN-I plays a critical role in the antiviral innate immune responses that protect host against virus infection. The negative regulators of IFN-I are not only important for fine-tuning the antiviral responses to pathogens but also for preventing excessive inflammation. Identification of negative regulators and study of their modulation in innate immune responses will lead to new strategies for the control of both viral and inflammatory diseases. Here, we report for the first time that LYAR behaves as a repressor of the host innate immune responses. We demonstrate that LYAR negatively regulates IFN-β mediated immune responses by inhibiting the DNA binding ability of IRF3. Our study reveals a common mechanism of LYAR promoting different virus replication and improves the knowledge of the host negative regulation of innate immune responses.