Reactome | Phosphorylation of IRF-3/IRF7 and their release from the activated TLR complex

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

Stable Identifier

R-HSA-166245

Type

Reaction [transition]

Species

Homo sapiens

Compartment

endosome membrane, cytosol

ReviewStatus

5/5

Locations in the PathwayBrowser

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Immune System (Homo sapiens)

- Innate Immune System (Homo sapiens)
  - Toll-like Receptor Cascades (Homo sapiens)
    - Toll Like Receptor 4 (TLR4) Cascade (Homo sapiens)
      - MyD88-independent TLR4 cascade (Homo sapiens)
        
        TRIF (TICAM1)-mediated TLR4 signaling (Homo sapiens)
        
        Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) (Homo sapiens)
        
        Phosphorylation of IRF-3/IRF7 and their release from the activated TLR complex (Homo sapiens)

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

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Human IRF-3 is activated through a two step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKK-i. 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 IRF-3 dimerization.

IRF-3 and IRF-7 transcription factors possess distinct structural characteristics; IRF-7 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
12692549	IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway Maniatis, T, Golenbock, DT, McWhirter, SM, Latz, E, Rowe, DC, Liao, SM, Fitzgerald, KA, Faia, KL, Coyle, AJ	Nat Immunol	2003
17526488	Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch McWhirter, SM, Maniatis, T, Harrison, SC, Panne, D	J Biol Chem	2007
14703513	Identification of Ser-386 of interferon regulatory factor 3 as critical Fujita, T, Inagaki, F, Takahashi, K, Yoneyama, M, Mori, M, Ito, T	J Biol Chem	2004