EGFR ‐mediated tyrosine phosphorylation of STING determines its trafficking route and cellular innate immunity functions

STING ( ST imulator of IN terferon Genes) mediates protective cellular response to microbial infection and tissue damage, but its aberrant activation can lead to autoinflammatory diseases. Upon ligand stimulation, the endoplasmic reticulum ( ER ) protein STING translocates to endosomes for induction of interferon production, while an alternate trafficking route delivers it directly to the autophagosomes. Here, we report that phosphorylation of a specific tyrosine residue in STING by the epidermal growth factor receptor ( EGFR ) is required for directing STING to endosomes, where it interacts with its downstream effector IRF 3. In the absence of EGFR ‐mediated phosphorylation, STING rapidly transits into autophagosomes, and IRF 3 activation, interferon production, and antiviral activity are compromised in cell cultures and mice, while autophagic activity is enhanced. Our observations illuminate a new connection between the tyrosine kinase activity of EGFR and innate immune functions of STING and suggest new experimental and therapeutic approaches for selective regulation of STING functions.