Journal
CURRENT BIOLOGY
Volume 17, Issue 16, Pages 1438-1443Publisher
CELL PRESS
DOI: 10.1016/j.cub.2007.07.041
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Funding
- Intramural NIH HHS Funding Source: Medline
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NF-kappa B essential modulator (NEMO), the regulatory subunit of the I kappa B kinase (IKK) that activates NF-kappa B, is essential for NF-KB activation [1]. 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 (TNF alpha)-induced NF-kappa B activation [2, 3]. Optineurin is a homolog of NEMO, and mutations in the optineurin gene are found in a subset of patients with glaucoma [4], a neurodegenerative disease involving the loss of retinal ganglion cells [5]. Although optineurin shares considerable homology with NEMO, in resting cells, it is not present in the high-molecular-weight complex containing IKK alpha and IKK beta, and optineurin cannot substitute for NEMO in lipopolysaccharide (LPS)-induced NF-KB activation [6]. On the other hand, the overexpression of optineurin blocks the protective effect of E3-14.7K on cell death caused by the overexpression of TNF alpha receptor 1 (TNFR1) [7]. 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 TNF alpha-induced NF-KB activation. This competition occurs at physiologic protein levels because microRNA silencing of optineurin resulted in markedly enhanced TNF alpha-induced NF-kappa B activity. These results reveal a physiologic role for optineurin in dampening TNF alpha signaling, and this role might provide an explanation for its association with glaucoma.
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