AI Article Synopsis
- NEMO is a key subunit of the IKK complex, which activates NF-κB by phosphorylating its inhibitors (IκBs) through polyubiquitin chains.
- The interaction of NEMO with Lys63-linked or linear polyUb leads to the formation of liquid-like droplets that facilitate IKK activation.
- Mutations in NEMO linked to human immunodeficiency disrupt its ability to phase separate, highlighting the importance of polyUb in activating the NF-κB signaling pathway.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402427 | PMC |
| http://dx.doi.org/10.1016/j.molcel.2022.03.037 | DOI Listing |
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