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.
Keywords: CALML6; IRF3; antiviral innate immunity; calmodulin-like 6; dimerization; interferon regulatory factor 3; phosphorylation.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.