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

The RNA-binding protein tristetraprolin (TTP) and the mRNA decay machinery selectively limit type I and type III interferon (IFN) mRNA levels at steady state and after stimulation. Loss of this pathway increases IFN mRNA poly(A) tail length, stability and translation, raising IFN expression enough to block SARS-CoV-2 infection in vitro and in vivo. A human TTP variant linked to autoimmunity shows reduced TTP levels and increased IFN signaling, and transient loss of mRNA decay primes innate memory for long-term antiviral protection.