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

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. [Display omitted] •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.