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.

EMBO J. 31, 3845–3855 and 3856–3870 (2012)