The Structural Basis of IRF-3 Activation upon Phosphorylation.
J Immunol
; 205(7): 1886-1896, 2020 10 01.
Article
in En
| MEDLINE
| ID: mdl-32826280
ABSTRACT
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-ß 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interferon-beta
/
CREB-Binding Protein
/
Interferon Regulatory Factor-3
Limits:
Animals
/
Humans
Language:
En
Journal:
J Immunol
Year:
2020
Type:
Article