摘要
Type I interferons such as interferon-beta （IFN-β） play essential roles in the host innate immune response to herpes simplex virus type I （HSV-1） infection. The transcription of type I interferon genes is controlled by nuclear factor-κB （NF-κB） and interferon regulatory factor （IRF） family members including IRF3. NF-κB activation depends on the phosphorylation of inhibitor of κB （IκB）, which triggers its ubiqitination and degradation. It has been reported that neddylation inhibition by a pharmacological agent MLN4924 potently suppresses lipopolysaccharide （LPS）-induced proinflammatory cytokine production with the accumulation of phosphorylated IκBa. However, the role of neddylation in type I interferon expression remains unknown. Here, we report that neddylation inhibition with MLN4924 or upon UBA3 deficiency led to accumulation of phosphorylated IκBa, impaired IκBa degradation, and impaired NF-κB nuclear translocation in the early phase of HSV-1 infection even though phosphorylation and nuclear translocation of IRF3 were not affected. The blockade of NF-κB nuclear translocation by neddylation inhibition becomes less efficient at the later time points of HSV-1 infection. Consequently, HSV- 1-induced early phase IFN-β production significantly decreased upon MLN4924 treatment and UBA3 deficiency. NF-κB inhibitor JSH-23 mimicked the effects of neddylation inhibition in the early phase of HSV-1 infection. Moreover, the effects of neddylation inhibition on HSV-1-induced early phase IFN-c production diminished in the presence of NF-κB inhibitor JSH-23. Thus, neddylation contributes to HSV-l-induced early phase IFN-β production through, at least partially, promoting NF-κB activation.
Type I interferons such as interferon-beta （IFN-β） play essential roles in the host innate immune response to herpes simplex virus type I （HSV-1） infection. The transcription of type I interferon genes is controlled by nuclear factor-κB （NF-κB） and interferon regulatory factor （IRF） family members including IRF3. NF-κB activation depends on the phosphorylation of inhibitor of κB （IκB）, which triggers its ubiqitination and degradation. It has been reported that neddylation inhibition by a pharmacological agent MLN4924 potently suppresses lipopolysaccharide （LPS）-induced proinflammatory cytokine production with the accumulation of phosphorylated IκBa. However, the role of neddylation in type I interferon expression remains unknown. Here, we report that neddylation inhibition with MLN4924 or upon UBA3 deficiency led to accumulation of phosphorylated IκBa, impaired IκBa degradation, and impaired NF-κB nuclear translocation in the early phase of HSV-1 infection even though phosphorylation and nuclear translocation of IRF3 were not affected. The blockade of NF-κB nuclear translocation by neddylation inhibition becomes less efficient at the later time points of HSV-1 infection. Consequently, HSV- 1-induced early phase IFN-β production significantly decreased upon MLN4924 treatment and UBA3 deficiency. NF-κB inhibitor JSH-23 mimicked the effects of neddylation inhibition in the early phase of HSV-1 infection. Moreover, the effects of neddylation inhibition on HSV-1-induced early phase IFN-c production diminished in the presence of NF-κB inhibitor JSH-23. Thus, neddylation contributes to HSV-l-induced early phase IFN-β production through, at least partially, promoting NF-κB activation.
