Reactome | CASP8 cleaves N4BP1 at D424, D490

CASP8 cleaves N4BP1 at D424, D490

Stable Identifier

R-HSA-9757951

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

Locations in the PathwayBrowser

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Immune System (Homo sapiens)

- Cytokine Signaling in Immune system (Homo sapiens)
  - Signaling by Interleukins (Homo sapiens)
    - Interleukin-1 family signaling (Homo sapiens)
      - Interleukin-1 signaling (Homo sapiens)
        
        TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)
- Innate Immune System (Homo sapiens)
  - Toll-like Receptor Cascades (Homo sapiens)
    - Toll Like Receptor 10 (TLR10) Cascade (Homo sapiens)
      - MyD88 cascade initiated on plasma membrane (Homo sapiens)
        
        TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)
    - Toll Like Receptor 2 (TLR2) Cascade (Homo sapiens)
      - Toll Like Receptor TLR1:TLR2 Cascade (Homo sapiens)
        
        MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Homo sapiens)
        
        TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)
      - Toll Like Receptor TLR6:TLR2 Cascade (Homo sapiens)
        
        MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Homo sapiens)
        
        TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)
    - Toll Like Receptor 3 (TLR3) Cascade (Homo sapiens)
      - TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)
    - Toll Like Receptor 4 (TLR4) Cascade (Homo sapiens)
      - MyD88-independent TLR4 cascade (Homo sapiens)
        
        TRIF (TICAM1)-mediated TLR4 signaling (Homo sapiens)
        
        TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)
      - MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Homo sapiens)
        
        TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)
    - Toll Like Receptor 5 (TLR5) Cascade (Homo sapiens)
      - MyD88 cascade initiated on plasma membrane (Homo sapiens)
        
        TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)
    - Toll Like Receptor 7/8 (TLR7/8) Cascade (Homo sapiens)
      - MyD88 dependent cascade initiated on endosome (Homo sapiens)
        
        TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (Homo sapiens)
        
        TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)
    - Toll Like Receptor 9 (TLR9) Cascade (Homo sapiens)
      - MyD88 dependent cascade initiated on endosome (Homo sapiens)
        
        TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (Homo sapiens)
        
        TAK1-dependent IKK and NF-kappa-B activation (Homo sapiens)
        
        Regulation of NF-kappa B signaling (Homo sapiens)
        
        CASP8 cleaves N4BP1 at D424, D490 (Homo sapiens)

General

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NEDD4-binding protein 1 (N4BP1) limits the activation of NF-kappaB downstream of TICAM1 (TRIF)-independent Toll-like receptor 2 (TLR2), TLR7 or TLR9 signaling pathways, but not upon engagement of TLR3 or TLR4 which utilize the adaptor protein TICAM1 (Shi H et al. 2021; Gitlin AD et al. 2020). TLR3- or TRL4-induced TICAM1-dependent activation of caspase-8 (CASP8) was found to inactivate N4BP1 via the proteolytic cleavage thus promoting NF-kappa-B activation (Gitlin AD et al. 2020; Shi H et al. 2021). Functional studies of N4BP1 mutants expressed in human embryonic kidney 293T (HEK293T) cells suggest that human N4BP1 is cleaved after D424 and/or D490 (Shi H et al. 2021).

Literature References

PubMed ID	Title	Journal	Year
33654074	N4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization Shi, H, Sun, L, Wang, Y, Liu, A, Zhan, X, Li, X, Tang, M, Anderton, P, Hildebrand, S, Quan, J, Ludwig, S, Moresco, EMY, Beutler, B	Nat Commun	2021