Prohibitin1 facilitates viral replication by impairing the RIG-I-like receptor signaling pathway

Abstract

ABSTRACT Innate immunity plays an essential role in defending the host against pathogenic infections. Appropriate controls are required to exert antiviral effects and avoid inflammatory disorders, but the negative regulation mechanisms are not fully understood. Here, Prohibitin1 (PHB1) was identified as a negative regulator of innate immune responses. We found that PHB1 protein and mRNA levels were promoted by virus-induced beta interferon (IFN-β) and subsequently suppressed the antiviral innate immune responses, thereby facilitating the replication of multiple RNA viruses. Further studies revealed that PHB1 interacted with IFN regulatory factor 3 (IRF3) to restrain the binding of IRF3 to nuclear import proteins, thereby suppressing the nuclear import of IRF3 and the downstream production of IFN-β. In summary, we elucidated the mechanism by which PHB1 regulates host antiviral innate immunity by inhibiting the nuclear translocation of IRF3, which contributed to the understanding of IRF3 regulation and revealed a novel role of PHB1 in host innate immunity. IMPORTANCE Type I interferon (IFN-I), produced by the innate immune system, plays an essential role in host antiviral responses. Proper regulation of IFN-I production is required for the host to balance immune responses and prevent superfluous inflammation. IFN regulatory factor 3 (IRF3) and subsequent sensors are activated by RNA virus infection to induce IFN-I production. Therefore, proper regulation of IRF3 serves as an important way to control innate immunity and viral replication. Here, we first identified Prohibitin1 (PHB1) as a negative regulator of host IFN-I innate immune responses. Mechanistically, PHB1 inhibited the nucleus import of IRF3 by impairing its binding with importin subunit alpha-1 and importin subunit alpha-5. Our study demonstrates the mechanism by which PHB1 facilitates the replication of multiple RNA viruses and provides insights into the negative regulation of host immune responses.