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

Mingjian Du, Chee Kwee Ea, Yan Fang, Zhijian Chen

Research output: Contribution to journalArticlepeer-review

Abstract

The NF-κB essential modulator (NEMO) is a regulatory subunit of the IκB kinase (IKK) complex that phosphorylates the NF-κB inhibitors IκBs. 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 multivalent 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-κB signaling by promoting the phase separation of NEMO.

Original languageEnglish (US)
Pages (from-to)2415-2426.e5
JournalMolecular cell
Volume82
Issue number13
DOIs
StatePublished - Jul 7 2022

Keywords

  • IKK
  • inflammation
  • innate immunity
  • liquid phase separation
  • NEMO
  • NF-κB
  • ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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