Phosphorylation of IRF-3/IRF7 and their release from the activated TLR3 complex

Stable Identifier
R-HSA-9013978
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Rotavirus, Influenza A virus, Hepatitis B virus, Hepatitis C Virus, Human herpesvirus 1
Compartment
endosome membrane, cytosol
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Phosphorylation of IRF-3/IRF7 and their release from the activated TLR3 complex
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Human IRF3 is activated through a two step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi. It requires Ser386 and/or Ser385 (site 1) and a cluster of serine/threonine residues between Ser396 and Ser405 (site 2) (Panne et al. 2007). Phosphorylated residues at site 2 alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1. Phosphorylation at site 1 is required for IRF3 dimerization.

IRF3 and IRF7 transcription factors possess distinct structural characteristics; IRF7 is phosphorylated on Ser477 and Ser479 residues (Lin R et al. 2000). TRAF6 mediated ubiquitination of IRF7 is also required and essential for IRF7 phosphorylation and activation. The K-63 linked ubiquitination occurs on the last three C-terminal lysine sites (positions 444, 446, and 452) of human IRF7 independently of its C-terminal functional phosphorylation sites.(Ning et al. 2008).

Literature References
PubMed ID Title Journal Year
17526488 Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch

Panne, D, McWhirter, SM, Maniatis, T, Harrison, SC

J Biol Chem 2007
12692549 IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway

Fitzgerald, KA, McWhirter, SM, Faia, KL, Rowe, DC, Latz, E, Golenbock, DT, Coyle, AJ, Liao, SM, Maniatis, T

Nat Immunol 2003
14703513 Identification of Ser-386 of interferon regulatory factor 3 as critical

Mori, M, Yoneyama, M, Ito, T, Takahashi, K, Inagaki, F, Fujita, T

J Biol Chem 2004
Participants
Input
Output
Participant Of
hasEvent
Catalyst Activity
Catalyst Activity
Title
protein serine/threonine kinase activity of activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7 [endosome membrane]
Physical Entity
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7 [endosome membrane]
Activity
protein serine/threonine kinase activity (0004674)
Authored
de Bono, B  (2005-08-16)
Reviewed
Gay, NJ  (2006-04-24)
Gillespie, ME  (2010-11-30)
Fitzgerald, KA  (2012-11-13)
Masci, A M  (2014-05-16)
Created
Shamovsky, V  (2017-07-26)