Curr Biol 2007,
PMID: 17702576
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
Document information provided by NCBI PubMed
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