RT Journal Article
SR Electronic
T1 Linear ubiquitination induces NEMO phase separation to activate NF-κB signaling
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202201607
DO 10.26508/lsa.202201607
VO 6
IS 4
A1 Simran Goel
A1 Rosario Oliva
A1 Sadasivam Jeganathan
A1 Verian Bader
A1 Laura J Krause
A1 Simon Kriegler
A1 Isabelle D Stender
A1 Chadwick W Christine
A1 Ken Nakamura
A1 Jan-Erik Hoffmann
A1 Roland Winter
A1 Jörg Tatzelt
A1 Konstanze F Winklhofer
YR 2023
UL https://www.life-science-alliance.org/content/6/4/e202201607.abstract
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.