Gene interactions and pathways from curated databases and text-mining
Curr Biol 2007, PMID: 17702576

Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP.

Zhu, Guozhi; Wu, Chuan-Jin; Zhao, Yongge; Ashwell, Jonathan D

NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase (IKK) that activates NF-kappaB, is essential for NF-kappaB activation. NEMO was recently found to contain a region that preferentially binds Lys (K)63-linked but not K48-linked polyubiquitin (polyUb) chains, and the ability of NEMO to bind to K63-linked polyUb RIP (receptor-interacting protein) is necessary for efficient tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. Optineurin is a homolog of NEMO, and mutations in the optineurin gene are found in a subset of patients with glaucoma, a neurodegenerative disease involving the loss of retinal ganglion cells. Although optineurin shares considerable homology with NEMO, in resting cells, it is not present in the high-molecular-weight complex containing IKKalpha and IKKbeta, and optineurin cannot substitute for NEMO in lipopolysaccharide (LPS)-induced NF-kappaB activation. On the other hand, the overexpression of optineurin blocks the protective effect of E3-14.7K on cell death caused by the overexpression of TNFalpha receptor 1 (TNFR1). Here we show that optineurin has a K63-linked polyUb-binding region similar to that of NEMO, and like NEMO, it bound K63- but not K48-linked polyUb. Optineurin competitively antagonized NEMO's binding to polyUb RIP, and its overexpression inhibited TNFalpha-induced NF-kappaB activation. This competition occurs at physiologic protein levels because microRNA silencing of optineurin resulted in markedly enhanced TNFalpha-induced NF-kappaB activity. These results reveal a physiologic role for optineurin in dampening TNFalpha signaling, and this role might provide an explanation for its association with glaucoma.

Diseases/Pathways annotated by Medline MESH: Glaucoma
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Text Mining Data

TNFalpha- → Optineurin: " Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP "

NF-kappaB → TNFalpha-: " Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP "

NF-kappaB → Optineurin: " Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP "

TNFalpha- — NEMO: " Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP "

Optineurin — NEMO: " Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP "

NF-kappaB — NEMO: " Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP "

NF-kappaB → IkappaB kinase (IKK): " NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase (IKK) that activates NF-kappaB , is essential for NF-kappaB activation "

NF-kappaB → NF-kappaB essential modulator (NEMO): " NF-kappaB essential modulator (NEMO) , the regulatory subunit of the IkappaB kinase (IKK) that activates NF-kappaB, is essential for NF-kappaB activation "

NF-kappaB → tumor necrosis factor alpha (TNFalpha): " NEMO was recently found to contain a region that preferentially binds Lys ( K ) 63-linked but not K48 linked polyubiquitin ( polyUb ) chains, and the ability of NEMO to bind to K63 linked polyUb RIP ( receptor interacting protein ) is necessary for efficient tumor necrosis factor alpha (TNFalpha) induced NF-kappaB activation "

NF-kappaB → lipopolysaccharide (LPS): " Although optineurin shares considerable homology with NEMO, in resting cells, it is not present in the high-molecular-weight complex containing IKKalpha and IKKbeta, and optineurin can not substitute for NEMO in lipopolysaccharide (LPS) induced NF-kappaB activation "

NF-kappaB ⊣ Optineurin: " Optineurin competitively antagonized NEMO 's binding to polyUb RIP, and its overexpression inhibited TNFalpha induced NF-kappaB activation "

NF-kappaB → TNFalpha: " Optineurin competitively antagonized NEMO 's binding to polyUb RIP, and its overexpression inhibited TNFalpha induced NF-kappaB activation "

NF-kappaB ⊣ optineurin: " This competition occurs at physiologic protein levels because microRNA silencing of optineurin resulted in markedly enhanced TNFalpha induced NF-kappaB activity "

NF-kappaB → TNFalpha: " This competition occurs at physiologic protein levels because microRNA silencing of optineurin resulted in markedly enhanced TNFalpha induced NF-kappaB activity "

Manually curated Databases

  • IRef Biogrid Interaction: RIPK1 — OPTN (direct interaction, pull down)
  • IRef Biogrid Interaction: RIPK1 — OPTN (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: UBC — OPTN (direct interaction, pull down)
  • IRef Biogrid Interaction: RIPK1 — IKBKG (direct interaction, pull down)
  • IRef Biogrid Interaction: RIPK1 — IKBKG (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: UBC — IKBKG (direct interaction, pull down)
  • IRef Biogrid Interaction: OPTN — TRADD (physical association, affinity chromatography technology)
  • IRef Innatedb Interaction: IKBKG — CHUK (unknown, -)
In total, 6 gene pairs are associated to this article in curated databases