Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation

Simin Rahighi, Fumiyo Ikeda, Masato Kawasaki, Masato Akutsu, Nobuhiro Suzuki, Ryuichi Kato, Tobias Kensche, Tamami Uejima, Stuart Bloor, David Komander, Felix Randow, Soichi Wakatsuki, Ivan Dikic

Research output: Contribution to journalArticle

458 Citations (Scopus)

Abstract

Activation of nuclear factor-κB (NF-κB), a key mediator of inducible transcription in immunity, requires binding of NF-κB essential modulator (NEMO) to ubiquitinated substrates. Here, we report that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO selectively binds linear (head-to-tail) ubiquitin chains. Crystal structures of the UBAN motif revealed a parallel coiled-coil dimer that formed a heterotetrameric complex with two linear diubiquitin molecules. The UBAN dimer contacted all four ubiquitin moieties, and the integrity of each binding site was required for efficient NF-κB activation. Binding occurred via a surface on the proximal ubiquitin moiety and the canonical Ile44 surface on the distal one, thereby providing specificity for linear chain recognition. Residues of NEMO involved in binding linear ubiquitin chains are required for NF-κB activation by TNF-α and other agonists, providing an explanation for the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency.

Original languageEnglish
Pages (from-to)1098-1109
Number of pages12
JournalCell
Volume136
Issue number6
DOIs
Publication statusPublished - Mar 20 2009
Externally publishedYes

Fingerprint

Ubiquitin
Modulators
Chemical activation
Dimers
Ectodermal Dysplasia
Transcription
Inpatients
Immunity
Crystal structure
Binding Sites
Mutation
Molecules
Substrates

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Rahighi, S., Ikeda, F., Kawasaki, M., Akutsu, M., Suzuki, N., Kato, R., ... Dikic, I. (2009). Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation. Cell, 136(6), 1098-1109. https://doi.org/10.1016/j.cell.2009.03.007

Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation. / Rahighi, Simin; Ikeda, Fumiyo; Kawasaki, Masato; Akutsu, Masato; Suzuki, Nobuhiro; Kato, Ryuichi; Kensche, Tobias; Uejima, Tamami; Bloor, Stuart; Komander, David; Randow, Felix; Wakatsuki, Soichi; Dikic, Ivan.

In: Cell, Vol. 136, No. 6, 20.03.2009, p. 1098-1109.

Research output: Contribution to journalArticle

Rahighi, S, Ikeda, F, Kawasaki, M, Akutsu, M, Suzuki, N, Kato, R, Kensche, T, Uejima, T, Bloor, S, Komander, D, Randow, F, Wakatsuki, S & Dikic, I 2009, 'Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation', Cell, vol. 136, no. 6, pp. 1098-1109. https://doi.org/10.1016/j.cell.2009.03.007
Rahighi, Simin ; Ikeda, Fumiyo ; Kawasaki, Masato ; Akutsu, Masato ; Suzuki, Nobuhiro ; Kato, Ryuichi ; Kensche, Tobias ; Uejima, Tamami ; Bloor, Stuart ; Komander, David ; Randow, Felix ; Wakatsuki, Soichi ; Dikic, Ivan. / Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation. In: Cell. 2009 ; Vol. 136, No. 6. pp. 1098-1109.
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