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Abstract #20591 Published in IGR 10-1
Optineurin Negatively Regulates TNFα- Induced NF-κB Activation by Competing with NEMO for Ubiquitinated RIP
Zhu G; Wu C-J; Zhao Y; Ashwell JDCurr Biol 2007; 17: 1438-1443
NF-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase (IKK) that activates NF-κB, is essential for NF-κB 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 α (TNFα)-induced NF-κB 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 IKKα and IKKβ, and optineurin cannot substitute for NEMO in lipopolysaccharide (LPS)-induced NF-κB 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 TNFα 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 TNFα-induced NF-κB activation. This competition occurs at physiologic protein levels because microRNA silencing of optineurin resulted in markedly enhanced TNFα-induced NF-κB activity. These results reveal a physiologic role for optineurin in dampening TNFα signaling, and this role might provide an explanation for its association with glaucoma.
Dr. J.D. Ashwell, Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. jda@pop.nci.nih.gov
Classification:
3.6 Cellular biology (Part of: 3 Laboratory methods)
3.7 Biochemistry (Part of: 3 Laboratory methods)
1.3 Pathogenesis (Part of: 1 General aspects)
