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

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.

Molecular and spatial mechanisms governing STING signalling

“…Therefore, these studies suggest that NF-jB has the ability to be activated at the ER before STING trafficking commences. Furthermore, phosphorylation of a STING tyrosine residue (Y245 in hSTING) by epidermal growth factor receptor (EGFR) has recently been shown to be important for appropriate trafficking of STING to endosomal regions for activation of IRF3 [148]. Treatment with EGFR inhibitors, including Gefitinib, or genetic ablation of EGFR promoted preferential association of STING with the autophagy marker LC3 and blocked IRF3 activation without effecting STING, TBK1 or NF-jB activation [148].…”

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

“…Thus the cGAS-STING signaling and autophagy induction impact each other positively and negatively may be depending on the qualities and properties of stimulating DNA or other host factors remaining to identify. The STING-dependent type 1 IFN production involves its translocation from the ER to the endosome that occurs through phosphorylation of the specific tyrosine residue (Y245) in the STING by the epidermal growth factor receptor (EGFR) ( 76 ). In the absence of STING phosphorylation through EGFR, it moves to the autophagosome where it degrades and no IRF3 activation dependent type 1 IFN production occurs as seen in vitro and in mice ( 76 ).…”

“…The STING-dependent type 1 IFN production involves its translocation from the ER to the endosome that occurs through phosphorylation of the specific tyrosine residue (Y245) in the STING by the epidermal growth factor receptor (EGFR) ( 76 ). In the absence of STING phosphorylation through EGFR, it moves to the autophagosome where it degrades and no IRF3 activation dependent type 1 IFN production occurs as seen in vitro and in mice ( 76 ). Hence, EGFR tyrosine kinase regulates cGAS-STING signaling-dependent type 1 IFN production through STING phosphorylation and promoting its translocation from the ER to the endosome.…”

Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

“…Since its discovery, this extracellular enzyme has aroused great interest because of its strong therapeutic potential ( 59 ) as inhibitors of ENPP1 could help potentiate cGAS-STING signaling ( 60 ). cGAS-STING pathway is also modulated by the epidermal growth factor receptor (EGFR) ( 61 ). EGFR is required for the phosphorylation of STING in the ER, leading to its endosomal translocation to activate IRF3 ( 61 ).…”

“…cGAS-STING pathway is also modulated by the epidermal growth factor receptor (EGFR) ( 61 ). EGFR is required for the phosphorylation of STING in the ER, leading to its endosomal translocation to activate IRF3 ( 61 ). In addition, the lysyl-tRNA synthetase has recently been identified as a potent modulator of the STING-dependent IFN pathway in a two-step mechanism ( 45 ).…”