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

Chenyao Wang, Xin Wang, Manoj Veleeparambil, Patricia M. Kessler, Belinda Willard, Saurabh Chattopadhyay, Ganes C. Sen

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere104106
JournalEMBO Journal
Volume39
Issue number22
DOIs
StatePublished - Nov 16 2020

Bibliographical note

Publisher Copyright:
© 2020 The Authors

Keywords

  • EGFR
  • IRF3
  • STING signaling
  • endosomes
  • tyrosine phosphorylation

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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