EGFR-mediated tyrosine phosphorylation ofSTINGdetermines its trafficking route and cellular innate immunity functions

STING(STimulator ofINterferon 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) proteinSTINGtranslocates 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 inSTINGby the epidermal growth factor receptor (EGFR) is required for directingSTINGto endosomes, where it interacts with its downstream effectorIRF3. In the absence ofEGFR-mediated phosphorylation,STINGrapidly transits into autophagosomes, andIRF3 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 ofEGFRand innate immune functions ofSTINGand suggest new experimental and therapeutic approaches for selective regulation ofSTINGfunctions.