Document Type
Article
Publication Date
4-2014
Abstract
The linear ubiquitin chain assembly complex (LUBAC) ligase, consisting of HOIL-1L, HOIP, and SHARPIN, specifically generates linear polyubiquitin chains. LUBAC-mediated linear polyubiquitination has been implicated in NF-κB activation. NEMO, a component of the IκB kinase (IKK) complex, is a substrate of LUBAC, but the precise molecular mechanism underlying linear chain-mediated NF-κB activation has not been fully elucidated. Here, we demonstrate that linearly polyubiquitinated NEMO activates IKK more potently than unanchored linear chains. In mutational analyses based on the crystal structure of the complex between the HOIP NZF1 and NEMO CC2-LZ domains, which are involved in the HOIP-NEMO interaction, NEMO mutations that impaired linear ubiquitin recognition activity and prevented recognition by LUBAC synergistically suppressed signal-induced NF-κB activation. HOIP NZF1 bound to NEMO and ubiquitin simultaneously, and HOIP NZF1 mutants defective in interaction with either NEMO or ubiquitin could not restore signal-induced NF-κB activation. Furthermore, linear chain-mediated activation of IKK2 involved homotypic interaction of the IKK2 kinase domain. Collectively, these results demonstrate that linear polyubiquitination of NEMO plays crucial roles in IKK activation and that this modification involves the HOIP NZF1 domain and recognition of NEMO-conjugated linear ubiquitin chains by NEMO on another IKK complex.
Recommended Citation
Hiroaki Fujita, Simin Rahighi, Mariko Akita, Ryuichi Kato, Yoshiteru Sasaki, Soichi Wakatsuki and Kazuhiro Iwai (2014). Mechanism underlying IKK activation mediated by the linear ubiquitin chain assembly complex (LUBAC). Mol. Cell Biol. 34 (7): 1322- 1335. doi: 10.1128/MCB.01538-13
Copyright
American Society for Microbiology
Included in
Amino Acids, Peptides, and Proteins Commons, Enzymes and Coenzymes Commons, Other Pharmacy and Pharmaceutical Sciences Commons
Comments
This article was originally published in Molecular and Cellular Biology, volume 34, issue 7, in 2014. DOI: 10.1128/MCB.01538-13