Molecular control of the NEMO family of ubiquitin-binding proteins

Key Points NF-κB essential modulator (NEMO) is an integral regulatory component of the canonical IκB kinase (IKK) complex that has key roles in controlling the activation of IKKα and IKKβ by ubiquitin chains and in substrate recognition. NEMO interacts with linear (Met1-linked) ubiquitin dimers through its UBAN (ubiquitin binding in ABIN and NEMO) domain. Disruption of this domain, for example by mutating Asp311 to Asn, prevents its recruitment to Met1-linked ubiquitin chains, reducing the activation of the canonical IKK complex by TGFβ-activated kinase 1 (TAK1) and the phosphorylation of its substrates. Most of the Met1-linked ubiquitin oligomers formed in response to interleukin-1 (IL-1) are attached covalently to Lys63-linked ubiquitin oligomers, which may facilitate the activation of the canonical IKK complex by TAK1. The NEMO–TANK (TRAF-associated NF-κB activator) complex facilitates crosstalk within the IKK family. Disruption of the complex interferes with the ability of the IKK-related kinases to limit the activation of the canonical IKKs, which is an important feedback control mechanism in vivo . By regulating the activation of TANK-binding kinase 1 (TBK1) and IKKɛ, NEMO also controls the activation of the transcription factor IFN regulatory factor 3 (IRF3), which is required for the production of type I interferons. The ubiquitin-binding domain of NEMO is also present in A20-binding inhibitor of NF-κB 1 (ABIN1), ABIN2, ABIN3 and optineurin, and ubiquitin binding to these proteins also regulates key molecular networks in the immune system. Nuclear factor-κB (NF-κB) signalling is tightly regulated through ubiquitylation and phosphorylation of its components. Integral to this post-translational regulation is the polyubiquitin-binding protein NF-κB essential modulator (NEMO), which controls the modification of numerous NF-κB signalling proteins, such as the canonical IκB kinase (IKKs) and IKK-related kinases. Research over the past decade has revealed how NF-κB essential modulator (NEMO; also known as IKKγ) regulates the IKKα–IKKβ signalling axis in the innate immune system. The discovery that NEMO is a polyubiquitin-binding protein and that the IKK complex is modulated by other protein kinases that are themselves controlled by polyubiquitin chains has provided a deeper molecular understanding of the non-degradative roles of ubiquitylation. New mechanistic insights of NEMO and related polyubiquitin-binding proteins have become a paradigm for how the i