AKT2 reduces IFNβ1 production to modulate antiviral responses and systemic lupus erythematosus

Interferon regulatory factor 3 (IRF3)‐induced type I interferon (I‐IFN) production plays key roles in both antiviral and autoimmune responses. IRF3 phosphorylation, dimerization, and nuclear localization are needed for its activation and function, but the precise regulatory mechanisms remain to be explored. Here, we show that the serine/threonine kinase AKT2 interacts with IRF3 and phosphorylates it on Thr207, thereby attenuating IRF3 nuclear translocation in a 14‐3‐3ε‐dependent manner and reducing I‐IFN production. We further find that AKT2 expression is downregulated in viral‐infected macrophages or in monocytes and tissue samples from systemic lupus erythematosus (SLE) patients and mouse models. Akt2 ‐deficient mice exhibit increased I‐IFN induction and reduced mortality in response to viral infection, but aggravated severity of SLE. Overexpression of AKT2 kinase‐inactive or IRF3‐T207A mutants in zebrafish supports that AKT2 negatively regulates I‐IFN production and antiviral response in a kinase‐dependent manner. This negative role of AKT2 in IRF3‐induced I‐IFN production suggests that AKT2 may be therapeutically targeted to differentially regulate antiviral infection and SLE. Synopsis Interferon regulatory factor 3 (IRF3)‐induced type I interferon (I‐IFN) production plays key roles during antiviral response and systemic lupus erythematosus (SLE). Here, AKT2 is shown to regulate I‐IFN production by binding to and phosphorylating IRF3 to attenuate IRF3 nuclear translocation, leading to reduced I‐IFN production. AKT2 expression is downregulated in viral‐infected macrophages and in samples from SLE patients and mouse models. I‐IFN stimulation reduces Akt2 transcription and AKT2 inhibits I‐IFN production. AKT2 binds and phosphorylates IRF3 at Thr207 to reduce IRF3 nuclear localization. Akt2 deficiency promotes IFNβ1 production to favor antiviral response while enhancing SLE in mouse models. Graphical Abstract AKT2 binds to and phosphorylates IRF3, blocking IRF3 nuclear translocation and thereby type I interferon production during viral infection and in systemic lupus erythematosus.