Sci. STKE, 28 August 2007
Immunology Optineurin Competes with NEMO
Nancy R. Gough
Science's STKE, AAAS, Washington, DC 20005 USA
Optineurin is a protein with sequence similarity to NEMO [nuclear factor-B (NF-B) essential modulator]. Thus, Zhu et al. explored whether optineurin also participates in NF-B signaling. NEMO is part of a kinase complex that is required for activation of NF-B and recognizes proteins that become polyubiquitinated [including those with the lysine 63 (K63) linkage] during NF-B activation. Surprisingly, Zhu et al. found that cells overexpressing optineurin exhibited diminished NF-B reporter gene expression triggered by overexpression of the upstream constituents TRAF2 (a ubiquitin ligase) or RIP (receptor interacting protein) in the NF-B signaling pathway or by treatment of the cells with tumor necrosis factor (TNF-). In addition, increasing expression of optineurin decreased the coimmunoprecipitation of NEMO and polyubiquitinated RIP in TNF--treated cells. Both NEMO and optineurin bound to beads coated with glutathione-S-transferase (GST)-ubiquitin fusion protein; however optineurin showed increased binding compared with NEMO to beads with the K63-linked ubiquitin. GST-NEMO and GST-optineurin both associated with polyubiquitinated RIP, and both NEMO and optineurin coimmunoprecipitated ubiquitinated RIP from TNF--treated cells. However, NEMO and optineurin were never coimmunoprecipitated, suggesting an exclusive interaction with target proteins. Indeed, increasing concentrations of optineurin reduced the interaction between polyubiquitinated RIP and GST-NEMO. RNA interference studies showed that when optineurin was depleted, the activation of an endogenous NF-B target gene, as well as a reporter gene, in response to TNF- was increased. Thus, optineurin appears to serve as a negative regulator of NF-B signaling by competing with NEMO for K63-linked polyubiquitinated proteins important for connecting activated receptors to NF-B activation.
G. Zhu, C.-J. Wu, Y. Zhao, J. D. Ashwell, Optineurin negatively regulates TNF-induced NF-B activation by competing with NEMO for ubiquitinated RIP. Current Biol. 17, 1438-1443 (2007). [PubMed]
Citation: N. R. Gough, Optineurin Competes with NEMO. Sci. STKE 2007, tw310 (2007).
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