EGFR-mediated tyrosine phosphorylation of STING determines its trafficking route and cellular innate immunity functions
| Autor: | Ganes C. Sen, Saurabh Chattopadhyay, Patricia M Kessler, Xin Wang, Belinda Willard, Manoj Veleeparambil, Chenyao Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Endosome Endosomes Biology Endoplasmic Reticulum General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Animals Humans Phosphorylation Molecular Biology 030304 developmental biology 0303 health sciences General Immunology and Microbiology Effector General Neuroscience Membrane Proteins Tyrosine phosphorylation Articles eye diseases Immunity Innate Cell biology ErbB Receptors Mice Inbred C57BL Sting Protein Transport RAW 264.7 Cells chemistry Stimulator of interferon genes Gene Knockdown Techniques Tyrosine Interferon Regulatory Factor-3 IRF3 Transcriptome Tyrosine kinase 030217 neurology & neurosurgery HeLa Cells Signal Transduction |
| Zdroj: | EMBO J |
| ISSN: | 1460-2075 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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