Selective decay of interferon mRNAs controls antiviral immunity and innate memory.

Homeostatic control of interferon (IFN) signaling is essential, as dysregulation leads to poor outcomes. While the stimuli-dependent induction of IFNs is well understood, less is known about how IFN mRNAs are maintained at low levels basally or rapidly returned to baseline post-stimulation. We find that selective post-transcriptional control of type I and type III IFN mRNAs by the RNA-binding specificity factor tristetraprolin (TTP) and mRNA decay machinery contributes to homeostatic control by negatively regulating IFN mRNAs at steady state and post-stimulation. Loss of this pathway leads to increased poly(A) tail length, stability, and translation. This increases expression of IFNs, potently blocking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro and in vivo. A human TTP variant associated with autoimmunity shows decreased TTP levels and increased IFN signaling, further demonstrating that regulation by this pathway impacts disease. Prolonged IFN signaling driven by transient loss of mRNA decay primes cells, inducing innate memory and providing long-term antiviral protection.