Liquid phase separation of NEMO induced by polyubiquitin chains activates NF-KB

The NF-KB essential modulator (NEMO) is a regulatory subunit of the IKB kinase (IKK) complex that phosphor-ylates the NF-KB inhibitors IKBs. NEMO mediates IKK activation by binding to polyubiquitin chains (polyUb). Here, we show that Lys63(K63)-linked or linear polyUb binding to NEMO robustly induced the formation of liquid-like droplets in which IKK was activated. This liquid phase separation of NEMO was driven by multiva-lent interactions between NEMO and polyUb. Both the NEMO ubiquitin-binding (NUB) domain and the zinc -finger (ZF) domain of NEMO mediated binding to polyUb and contributed to NEMO phase separation and IKK activation in cells. Moreover, NEMO mutations associated with human immunodeficiency impaired its phase separation. These results demonstrate that polyUb activates IKK and NF-KB signaling by promoting the phase separation of NEMO.

Automated summary

NEMO acts as a regulatory subunit of the IKK complex and is activated by binding to polyubiquitin chains (polyUb), leading to the formation of liquid-like droplets and activation of IKK and NF-KB signaling.