Analysis of Nuclear Factor-kappa B (NF-kappa B) Essential Modulator (NEMO) Binding to Linear and Lysine-linked Ubiquitin Chains and Its Role in the Activation of NF-kappa B

作者：Kensche Tobias; Tokunaga Fuminori; Ikeda Fumiyo; Goto Eiji; Iwai Kazuhiro; Dikic Ivan^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287(28): 23626-23634.

DOI：10.1074/jbc.M112.347195

Nuclear factor-kappa B (NF-kappa B) essential modulator (NEMO), a component of the inhibitor of kappa B kinase (IKK) complex, controls NF-kappa B signaling by binding to ubiquitin chains. Structural studies of NEMO provided a rationale for the specific binding between the UBAN (ubiquitin binding in ABIN and NEMO) domain of NEMO and linear (Met-1-linked) di-ubiquitin chains. Full-length NEMO can also interact with Lys-11-, Lys-48-, and Lys-63-linked ubiquitin chains of varying length in cells. Here, we show that purified full-length NEMO binds preferentially to linear ubiquitin chains in competition with lysine-linked ubiquitin chains of defined length, including long Lys-63-linked deca-ubiquitins. Linear di-ubiquitins were sufficient to activate both the IKK complex in vitro and to trigger maximal NF-kappa B activation in cells. In TNF alpha-stimulated cells, NEMO chimeras engineered to bind exclusively to Lys-63-linked ubiquitin chains mediated partial NF-kappa B activation compared with cells expressing NEMO that binds to linear ubiquitin chains. We propose that NEMO functions as a high affinity receptor for linear ubiquitin chains and a low affinity receptor for long lysine-linked ubiquitin chains. This phenomenon could explain quantitatively distinct NF-kappa B activation patterns in response to numerous cell stimuli.

• 出版日期2012-7-6