The Structural Basis of IRF-3 Activation upon Phosphorylation. Academic Article uri icon


  • 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 pSer386 (pSer379 in mouse IRF-3) and a downstream pLxIS motif. Size-exclusion chromatography and cell-based studies show that mutations of key residues interacting with pSer386 severely impair IRF-3 activation and IFN- induction. By contrast, phosphorylation of Ser396 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.

published proceedings

  • J Immunol

altmetric score

  • 1

author list (cited authors)

  • Jing, T., Zhao, B., Xu, P., Gao, X., Chi, L., Han, H., Sankaran, B., & Li, P.

citation count

  • 9

complete list of authors

  • Jing, Tao||Zhao, Baoyu||Xu, Pengbiao||Gao, Xinsheng||Chi, Lei||Han, Huajun||Sankaran, Banumathi||Li, Pingwei

publication date

  • October 2020