| First Author | Jing T | Year | 2020 |
| Journal | J Immunol | Volume | 205 |
| Issue | 7 | Pages | 1886-1896 |
| PubMed ID | 32826280 | Mgi Jnum | J:303582 |
| Mgi Id | MGI:6502449 | Doi | 10.4049/jimmunol.2000026 |
| Citation | Jing T, et al. (2020) The Structural Basis of IRF-3 Activation upon Phosphorylation. J Immunol 205(7):1886-1896 |
| abstractText | The innate immune system is the first line of defense against bacterial and viral infections. The recognition of pathogen-associated molecular patterns by the RIG-I-like receptors, TLRs, and cGAS leads to the induction of IFN-I by activating the transcription factor IRF-3. Although the mechanism of IRF-3 activation has been extensively studied, the structural basis of IRF-3 activation upon phosphorylation is not fully understood. In this study, we determined the crystal structures of phosphorylated human and mouse IRF-3 bound to CREB-binding protein (CBP), which reveal that phosphorylated IRF-3 forms a dimer via pSer(386) (pSer(379) in mouse IRF-3) and a downstream pLxIS motif. Size-exclusion chromatography and cell-based studies show that mutations of key residues interacting with pSer(386) severely impair IRF-3 activation and IFN-beta induction. By contrast, phosphorylation of Ser(396) within the pLxIS motif of human IRF-3 only plays a moderate role in IRF-3 activation. The mouse IRF-3/CBP complex structure reveals that the mechanism of mouse IRF-3 activation is similar but distinct from human IRF-3. These structural and functional studies reveal the detailed mechanism of IRF-3 activation upon phosphorylation. |
