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Molecular control of the NEMO family of ubiquitin-binding proteins

Nature Reviews Molecular Cell Biology volume 14, pages 673–685 (2013)Cite this article

Subjects

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.

Abstract

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 interplay between phosphorylation and ubiquitylation controls cell signalling networks in health and disease.

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Figure 1: Colocalization of the TAK1 and canonical IKK complexes on Met1- and Lys63-linked hybrid ubiquitin molecules in response to IL-1.
Figure 2: Negative regulation of the canonical and non-canonical IKK complexes by IKK-related kinases.
Figure 3: Key amino acid residues mediating ubiquitin binding to NEMO and related proteins.

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Acknowledgements

The research in the authors' laboratory is supported by a Wellcome Trust Senior Investigator Award (to P.C.) and by the UK Medical Research Council, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, Merck-Serono and Pfizer.

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  1. Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee, DD1 5EH, Scotland, UK

    Kristopher Clark, Sambit Nanda & Philip Cohen

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  1. Kristopher Clark
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  2. Sambit Nanda
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Correspondence to Philip Cohen.

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Glossary

UBC13–UEV1A

The E2 conjugating enzyme that directs the formation of Lys63-linked polyubiquitin.

Systemic lupus erythematosus

A chronic and systemic autoimmune disease caused when the immune system attacks healthy tissues, resulting in tissue and organ damage.

Paget's disease

A chronic disease caused by abnormal bone regeneration, leading to the formation of enlarged, weak and brittle bones.

Amyotrophic lateral sclerosis

(ALS). A progressive and fatal motor neuron disorder that affects the function of voluntary muscles, leading to an inability to move, swallow, speak and breathe.

Normal tension glaucoma

A form of glaucoma caused by progressive damage to the optic nerve and associated loss of vision, but without any increase in the intraocular pressure found in other types of glaucoma.

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Clark, K., Nanda, S. & Cohen, P. Molecular control of the NEMO family of ubiquitin-binding proteins. Nat Rev Mol Cell Biol 14, 673–685 (2013). https://doi.org/10.1038/nrm3644

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