LYAR Suppresses Beta Interferon Induction by Targeting Phosphorylated Interferon Regulatory Factor 3

Abstract

The innate immune response is vital for host defense and must be tightly controlled, but the mechanisms responsible for its negative regulation are not fully understood. The cell growth-regulating nucleolar protein LYAR was found to promote replication of multiple viruses in our previous study. Here, we report that LYAR acts as a negative regulator of innate immune responses. We found that LYAR expression is induced by beta interferon (IFN-β) during virus infection. Further studies showed that LYAR interacts with phosphorylated IFN regulatory factor 3 (IRF3) to impede the DNA binding capacity of IRF3, thereby suppressing the transcription of IFN-β and 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 in 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 host innate immunity. IMPORTANCE Type I interferon (IFN-I) plays a critical role in the antiviral innate immune responses that protect the host against virus infection. The negative regulators of IFN-I are important not only 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 the cell growth-regulating nucleolar protein LYAR behaves as a repressor of host innate immune responses. We demonstrate that LYAR negatively regulates IFN-β-mediated immune responses by inhibiting the DNA binding ability of IFN regulatory factor 3 (IRF3). Our study reveals a common mechanism of LYAR in promoting different virus replication events and improves our knowledge of host negative regulation of innate immune responses.

Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2

“…The second major population of Nsp1-bound 80S ribosomes (Fig. 2, M and N) contained the cell growth regulating nucleolar protein LYAR, which was previously implicated in processing of pre-rRNA and in negative regulation of antiviral innate immune response (34,35). We found the C-terminus of LYAR occupying the ribosomal A-site, similar to CCDC124 (Fig.…”

Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression

“…Nuclear import is repressed by the increasing interaction of IRF3 with the IFN-inducible DEAD-box RNA helicase DDX56, as this interaction competes with the association of IRF3 and IPO5 [ 163 ]. The IRF3-DNA interaction is inhibited by interaction of newly synthesized cell growth-regulating nucleolar protein LYAR (Ly1 antibody-reactive), which is usually low expressed in most cell tissues but induced by the IFNβ response [ 164 ]. LYAR interacts specifically with the N-terminal domain of activated IRF3 and in this way interferes with the DNA-binding capacity of IRF3 in the IRF3-CBP/p300 holocomplex.…”

Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2

“…The second major population of Nsp1-bound 80S ribosomes ( Fig. 2, M and N ) lacked CCDC124, but contained the cell growth regulating nucleolar protein LYAR, which has been implicated in processing of pre-rRNA and in negative regulation of antiviral innate immune responses ( 34 , 35 ). We found the C terminus of LYAR occupying the ribosomal A-site, similar to CCDC124 ( Fig.…”