Optineurin Competes with NEMO

Science's STKE  28 Aug 2007:
Vol. 2007, Issue 401, pp. tw310
DOI: 10.1126/stke.4012007tw310

Optineurin is a protein with sequence similarity to NEMO [nuclear factor-κB (NF-κB) essential modulator]. Thus, Zhu et al. explored whether optineurin also participates in NF-κB signaling. NEMO is part of a kinase complex that is required for activation of NF-κB and recognizes proteins that become polyubiquitinated [including those with the lysine 63 (K63) linkage] during NF-κB activation. Surprisingly, Zhu et al. found that cells overexpressing optineurin exhibited diminished NF-κB reporter gene expression triggered by overexpression of the upstream constituents TRAF2 (a ubiquitin ligase) or RIP (receptor interacting protein) in the NF-κB signaling pathway or by treatment of the cells with tumor necrosis factor α (TNF-α). In addition, increasing expression of optineurin decreased the coimmunoprecipitation of NEMO and polyubiquitinated RIP in TNF-α-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-α-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-κB target gene, as well as a reporter gene, in response to TNF-α was increased. Thus, optineurin appears to serve as a negative regulator of NF-κB signaling by competing with NEMO for K63-linked polyubiquitinated proteins important for connecting activated receptors to NF-κB activation.

G. Zhu, C.-J. Wu, Y. Zhao, J. D. Ashwell, Optineurin negatively regulates TNFα-induced NF-κB activation by competing with NEMO for ubiquitinated RIP. Current Biol. 17, 1438-1443 (2007). [PubMed]