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

EMBO J. 2020 Nov 16;39(22):e104106. doi: 10.15252/embj.2019104106. Epub 2020 Sep 14.


STING (STimulator of INterferon 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 IRF3. In the absence of EGFR-mediated phosphorylation, STING rapidly transits into autophagosomes, and IRF3 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.

Keywords: EGFR; IRF3; STING signaling; endosomes; tyrosine phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Endoplasmic Reticulum / metabolism
  • Endosomes / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Immunity, Innate* / genetics
  • Interferon Regulatory Factor-3 / genetics
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Transport / physiology*
  • RAW 264.7 Cells
  • Signal Transduction
  • Transcriptome
  • Tyrosine / metabolism*


  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Tyrosine
  • EGFR protein, human
  • EGFR protein, mouse
  • ErbB Receptors