Epidermal growth factor receptor is essential for Toll-like receptor 3 signaling.
Toll-like receptors (TLRs) recognize specific microbial products and elicit innate immune signals to activate specific transcription factors that induce protective proteins, such as interferon. TLR3 is localized to endosomes and recognizes double-stranded RNA (dsRNA), which is generated by virally infected or apoptotic cells. TLR3 has been genetically linked to several human diseases, including some without viral etiology. Unlike other TLRs, TLR3 requires phosphorylation of two specific tyrosine residues in its cytoplasmic domain to recruit the adaptor protein TRIF (Toll-interleukin-1 receptor domain-containing adaptor protein inducing interferon-β) and initiate the antiviral response. We showed that two protein tyrosine kinases, the epidermal growth factor receptor (EGFR) ErbB1 and Src, bound sequentially to dsRNA-activated TLR3 and phosphorylated the two tyrosine residues. In cells lacking EGFR or treated with an inhibitor of EGFR, viral replication was enhanced and induction of antiviral genes was impaired. Thus, these results reveal a connection between antiviral innate immunity and cell growth regulators.
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE20, Cleveland, OH 44195, USA.
Michifumi
M
Yamashita
Saurabh
S
Chattopadhyay
Volker
V
Fensterl
Paramananda
P
Saikia
Jaime L
JL
Wetzel
Ganes C
GC
Sen
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005822:Genetic Vectors; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D018613:Microscopy, Confocal; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D014777:Virus Diseases / Q000276:immunology*; D019061:src-Family Kinases / Q000378:metabolism*
D017931:DNA Primers; D034741:RNA, Small Interfering; D051196:Toll-Like Receptor 3; D066246:ErbB Receptors; D019061:src-Family Kinases