Linear polyubiquitination is mediated by the LUBAC protein complex and can direct signaling by the transcription factor NF-kB; however, the regulation of LUBAC-mediated linear ubiquitination is unclear. Two papers in EMBO Journal, by Beyaert et al. and Nureki et al., demonstrate how the deubiquitinating factor A20 can control LUBAC function and NF-kB activity. Both groups find that A20 rapidly associates with LUBAC polyubiquitination chains after triggering of the receptor for tumor-necrosis factor and arrest NF-kB signaling. This inhibition seems to operate through the ability of A20 to compete with binding of the NF-kB pathway adaptor NEMO to LUBAC. The seventh zinc-finger domain of A20 (ZF7) is crucial for the association with LUBAC, and ZF7 polypeptides alone are sufficient to regulate NF-kB. Nureki et al. crystallize the ZF7–linear polyubiquitin complex and observe that binding occurs via a structure formed by two connected ubiquitin units. This mechanism of NF-kB regulation therefore seems to operate independently of its deubiquitination activity.
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Fehervari, Z. Regulating LUBAC. Nat Immunol 13, 1143 (2012). https://doi.org/10.1038/ni.2483
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DOI: https://doi.org/10.1038/ni.2483