Linear ubiquitination induces NEMO phase separation to
activate NF-\(\kappa\)B signaling

The NF-\(\kappa\)B essential modulator NEMO is the core regulatory component of the inhibitor of \(\kappa\)B kinase complex, which is a critical checkpoint in canonical NF-\(\kappa\)B signaling downstream of innate and adaptive immune receptors. In response to various stimuli, such as TNF or IL-1\(\beta\), NEMO binds to linear or M1-linked ubiquitin chains generated by LUBAC, promoting its oligomerization and subsequent activation of the associated kinases. Here we show that M1-ubiquitin chains induce phase separation of NEMO and the formation of NEMO assemblies in cells after exposure to IL-1\(\beta\). Phase separation is promoted by both binding of NEMO to linear ubiquitin chains and covalent linkage of M1-ubiquitin to NEMO and is essential but not sufficient for its phase separation. Supporting the functional relevance of NEMO phase separation in signaling, a pathogenic NEMO mutant, which is impaired in both binding and linkage to linear ubiquitin chains, does not undergo phase separation and is defective in mediating IL-1\(\beta\)–induced NF-\(\kappa\)B activation.

Metadaten
Author:	Simran Goel ORCiD GND, Rosario Oliva GND, Sadasivam Jeganathan ORCiD GND, Verian Bader ORCiD GND, Laura J. Krause ORCiD GND, Simon Kriegler GND, Isabelle D. Stender GND, Chadwick W. Christine ORCiD GND, Ken Nakamura GND, Jan-Erik Hoffmann ORCiD GND, Roland Winter ORCiD GND, Jörg Tatzelt ORCiD GND, Konstanze Winklhofer ORCiD GND
URN:	urn:nbn:de:hbz:294-104843
DOI:	https://doi.org/10.26508/lsa.202201607
Parent Title (English):	Life science alliance
Publisher:	Life Science Alliance LLC
Document Type:	Article
Language:	English
Date of Publication (online):	2023/11/28
Date of first Publication:	2023/01/31
Publishing Institution:	Ruhr-Universität Bochum, Universitätsbibliothek
Tag:	Open Access Fonds
Volume:	6
Issue:	4, Artikel e202201607
First Page:	e202201607-1
Last Page:	e202201607-18
Note:	Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum.
Institutes/Facilities:	Institut für Biochemie und Pathobiochemie, Abteilung für Molekulare Zellbiologie
Dewey Decimal Classification:	Naturwissenschaften und Mathematik / Chemie, Kristallographie, Mineralogie
open_access (DINI-Set):	open_access
faculties:	Fakultät für Chemie und Biochemie
Licence (English):	Creative Commons - CC BY 4.0 - Attribution 4.0 International

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