@article{1e32fe75b0cb4507b804093b237cacd7,
title = "Liquid phase separation of NEMO induced by polyubiquitin chains activates NF-κB",
abstract = "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.",
keywords = "IKK, inflammation, innate immunity, liquid phase separation, NEMO, NF-κB, ubiquitin",
author = "Mingjian Du and Ea, {Chee Kwee} and Yan Fang and Zhijian Chen",
note = "Funding Information: We thank the UT Southwestern Live Cell Imaging Facility for assistance in our imaging experiments. This work was supported by grants to Z.J.C. from the Cancer Prevention and Research Institute of Texas ( RP180725 ) and the Welch Foundation ( I-1389 ). Y.F. was supported by a predoctoral training grant from the Cancer Prevention and Research Institute of Texas ( RP210041 ). Z.J.C. is an investigator of the Howard Hughes Medical Institute . Funding Information: We thank the UT Southwestern Live Cell Imaging Facility for assistance in our imaging experiments. This work was supported by grants to Z.J.C. from the Cancer Prevention and Research Institute of Texas (RP180725) and the Welch Foundation (I-1389). Y.F. was supported by a predoctoral training grant from the Cancer Prevention and Research Institute of Texas (RP210041). Z.J.C. is an investigator of the Howard Hughes Medical Institute. M.D. and Z.J.C. conceptualized the project. M.D. C.E. and Y.F. designed and performed experiments. M.D. and Z.J.C. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = jul,
day = "7",
doi = "10.1016/j.molcel.2022.03.037",
language = "English (US)",
volume = "82",
pages = "2415--2426.e5",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "13",
}