EGFR-mediated tyrosine phosphorylation of STING determines its trafficking route and cellular innate immunity functions.
Animals
Cell Line
Endoplasmic Reticulum
/ metabolism
Endosomes
/ metabolism
ErbB Receptors
/ genetics
Gene Knockdown Techniques
HeLa Cells
Humans
Immunity, Innate
/ genetics
Interferon Regulatory Factor-3
/ genetics
Male
Membrane Proteins
/ genetics
Mice
Mice, Inbred C57BL
Phosphorylation
Protein Transport
/ physiology
RAW 264.7 Cells
Signal Transduction
Transcriptome
Tyrosine
/ metabolism
EGFR
IRF3
STING signaling
endosomes
tyrosine phosphorylation
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
16 11 2020
16 11 2020
Historique:
received:
25
11
2019
revised:
16
07
2020
accepted:
14
08
2020
pubmed:
15
9
2020
medline:
15
4
2021
entrez:
14
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32926474
doi: 10.15252/embj.2019104106
pmc: PMC7667877
doi:
Substances chimiques
IRF3 protein, human
0
Interferon Regulatory Factor-3
0
Irf3 protein, mouse
0
Membrane Proteins
0
STING1 protein, human
0
Sting1 protein, mouse
0
Tyrosine
42HK56048U
EGFR protein, human
EC 2.7.10.1
EGFR protein, mouse
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e104106Subventions
Organisme : HHS | NIH | National Cancer Institute (NCI)
ID : CA062220
Organisme : NIH HHS
ID : S10 OD023436
Pays : United States
Organisme : HHS | NIH | National Cancer Institute (NCI)
ID : CA068782
Organisme : HHS | National Institutes of Health (NIH)
ID : 1S10OD023436-01
Organisme : NCI NIH HHS
ID : P01 CA062220
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA068782
Pays : United States
Informations de copyright
© 2020 The Authors.
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