AKT2 reduces IFNβ1 production to modulate anti-viral responses and systemic lupus erythematosus

ABSTRACT: Interferon regulatory factor 3 (IRF3)-induced type I interferon (I-IFN) production plays key roles in both anti-viral 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 anti-viral response in a kinase-dependent manner. This negative role of AKT2 in IRF3-induced I-IFN production suggests that it AKT2 may be therapeutically targeted to differentially regulate anti-viral infection and SLE.

SUBMITTER: Dr. Hongyan Wang 

PROVIDER: S-SCDT-EMBOJ-2021-108016 | biostudies-other |

REPOSITORIES: biostudies-other