Goel S, Oliva R, Jeganathan S, Bader V, Krause LJ, Kriegler S, Stender ID, Christine CW, Nakamura K, Hoffmann JE, Winter R, Tatzelt J, Winklhofer KF

The NF-?B essential modulator NEMO is the core regulatory component of the inhibitor of ?B kinase complex, which is a critical checkpoint in canonical NF-?B signaling downstream of innate and adaptive immune receptors. In response to various stimuli, such as TNF or IL-1?, NEMO binds to linear or M1-linked ubiquitin ...

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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?. 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?-induced NF-?B activation.

Date: Apr. 01, 2023

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