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EGFR ‐mediated tyrosine phosphorylation of STING determines its trafficking route and cellular innate immunity functions
Author(s) -
Wang Chenyao,
Wang Xin,
Veleeparambil Manoj,
Kessler Patricia M,
Willard Belinda,
Chattopadhyay Saurabh,
Sen Ganes C
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019104106
Subject(s) - biology , innate immune system , phosphorylation , sting , microbiology and biotechnology , tyrosine , immunity , tyrosine phosphorylation , immunology , immune system , biochemistry , aerospace engineering , engineering
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.