PT  - JOURNAL ARTICLE
AU  - Simran Goel
AU  - Rosario Oliva
AU  - Sadasivam Jeganathan
AU  - Verian Bader
AU  - Laura J Krause
AU  - Simon Kriegler
AU  - Isabelle D Stender
AU  - Chadwick W Christine
AU  - Ken Nakamura
AU  - Jan-Erik Hoffmann
AU  - Roland Winter
AU  - Jörg Tatzelt
AU  - Konstanze F Winklhofer
TI  - Linear ubiquitination induces NEMO phase separation to activate NF-κB signaling
AID  - 10.26508/lsa.202201607
DP  - 2023 Apr 01
TA  - Life Science Alliance
PG  - e202201607
VI  - 6
IP  - 4
4099  - https://www.life-science-alliance.org/content/6/4/e202201607.short
4100  - https://www.life-science-alliance.org/content/6/4/e202201607.full
SO  - Life Sci. Alliance2023 Apr 01; 6
AB  - The NF-κB essential modulator NEMO is the core regulatory component of the inhibitor of κB kinase complex, which is a critical checkpoint in canonical NF-κB signaling downstream of innate and adaptive immune receptors. In response to various stimuli, such as TNF or IL-1β, 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-1β. 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-1β–induced NF-κB activation.