The EF-Hand Protein CALML6 Suppresses Antiviral Innate Immunity by Impairing IRF3 Dimerization.

Summary The transcription factor IRF3 is phosphorylated in response to viral infection, and it subsequently forms a homodimer and translocates into the nucleus to induce the transcription of genes important for antiviral immunity, such as type I interferons (IFNs). This multistep process is essential for host defense against viral infection, but its regulation remains elusive. Here, we report that the EF-hand protein calmodulin-like 6 (CALML6) directly bound to the phosphorylated serine-rich (SR) region of IRF3 and impaired its dimerization and nuclear translocation. Enforced CALML6 expression suppressed viral infection-induced production of IFN-β and expression of IFN-stimulated genes (ISGs), whereas CALML6 deficiency had the opposite effect. In addition, impaired IFN-β and ISG expression in bone-marrow-derived macrophages and tissues of CALML6 transgenic mice promoted viral replication. These findings identify a phosphorylation-dependent negative feedback loop that maintains the homeostasis of antiviral innate immunity. Graphical Abstract Highlights • CALML6 attenuates type I interferon signaling in vitro and in vivo • CALML6 binds to phosphorylated IRF3 and sequesters it in the cytosol • CALML6 facilitates the replication of both DNA and RNA viruses Wang et al. report that the EF-hand protein CALML6 binds to the phosphorylated serine-rich region of IRF3 to impair IRF3 dimerization and nuclear translocation, thereby attenuating the transcription of type I interferons. This work identifies a negative feedback regulatory loop that maintains homeostasis during antiviral innate immunity. [ABSTRACT FROM AUTHOR]