Liquid Phase Separation of NEMO Induced by Polyubiquitin Chains Activates NF-κB

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...

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Autores principales: Du, Mingjian, Ea, Chee-Kwee, Fang, Yan, Chen, Zhijian J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402427/
https://www.ncbi.nlm.nih.gov/pubmed/35477005
http://dx.doi.org/10.1016/j.molcel.2022.03.037
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author Du, Mingjian
Ea, Chee-Kwee
Fang, Yan
Chen, Zhijian J.
author_facet Du, Mingjian
Ea, Chee-Kwee
Fang, Yan
Chen, Zhijian J.
author_sort Du, Mingjian
collection PubMed
description 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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spelling pubmed-94024272022-08-25 Liquid Phase Separation of NEMO Induced by Polyubiquitin Chains Activates NF-κB Du, Mingjian Ea, Chee-Kwee Fang, Yan Chen, Zhijian J. Mol Cell Article 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. 2022-07-07 2022-04-26 /pmc/articles/PMC9402427/ /pubmed/35477005 http://dx.doi.org/10.1016/j.molcel.2022.03.037 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Du, Mingjian
Ea, Chee-Kwee
Fang, Yan
Chen, Zhijian J.
Liquid Phase Separation of NEMO Induced by Polyubiquitin Chains Activates NF-κB
title Liquid Phase Separation of NEMO Induced by Polyubiquitin Chains Activates NF-κB
title_full Liquid Phase Separation of NEMO Induced by Polyubiquitin Chains Activates NF-κB
title_fullStr Liquid Phase Separation of NEMO Induced by Polyubiquitin Chains Activates NF-κB
title_full_unstemmed Liquid Phase Separation of NEMO Induced by Polyubiquitin Chains Activates NF-κB
title_short Liquid Phase Separation of NEMO Induced by Polyubiquitin Chains Activates NF-κB
title_sort liquid phase separation of nemo induced by polyubiquitin chains activates nf-κb
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402427/
https://www.ncbi.nlm.nih.gov/pubmed/35477005
http://dx.doi.org/10.1016/j.molcel.2022.03.037
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