Regulation of Met1-linked polyubiquitin signalling by the deubiquitinase OTULIN
Authors: Elliott, Paul R.; Komander, David
Modification of proteins with Met1-linked linear' ubiquitin chains has emerged as a key regulatory signal to control inflammatory signalling via the master regulator, the transcription factor nuclear factor B (NF-B). While the assembly machinery, the linear ubiquitin chain assembly complex (LUBAC), and receptors for this ubiquitin chain type have been known for years, it was less clear which deubiquitinating enzymes (DUBs) hydrolyse Met1 linkages specifically. In 2013, two labs reported the previously unannotated protein FAM105B/OTULIN to be this missing Met1 linkage-specific DUB. Structural studies have revealed how OTULIN achieves its remarkable specificity, employing a mechanism of ubiquitin-assisted catalysis in which a glutamate residue on the substrate complements the active site of the enzyme. The specificity of OTULIN enables it to regulate global levels of Met1-linked polyubiquitin in cells. This ability led to investigations of NF-B activation from new angles, and also revealed involvement of Met1-polyubiquitin in Wnt signalling. Interestingly, OTULIN directly interacts with LUBAC, and this interaction is dynamic and can be regulated by OTULIN phosphorylation. This provides a new paradigm for how individual linkage types can be regulated by dedicated enzyme complexes mediating assembly and removal. Here we review what has been learned about OTULIN's mechanism, regulation and function, discuss the open questions in the field, and discuss how DUBs regulate the NF-B response.
Regulation of Linear Ubiquitin Chain Assembly Complex by Caspase-Mediated Cleavage of RNF31
MOLECULAR AND CELLULAR BIOLOGY
Authors: Joo, Donghyun; Tang, Yong; Blonska, Marzenna; Jin, Jianping; Zhao, Xueqiang; Lin, Xin
Cell death and survival signaling pathways have opposed but fundamental functions for various cellular processes and maintain cell homeostasis through cross talk. Here we report a novel mechanism of interaction between these two pathways through the cleavage of RNF31 by caspases. RNF31, a component of the linear ubiquitin chain assembly complex (LUBAC), regulates cell survival by inducing linear ubiquitination of NF-kappa B signaling components. We found that RNF31 is cleaved under apoptosis conditions through various stimulations. The effector caspases caspase 3 and caspase 6 are responsible for this event, and aspartates 348, 387, and 390 were identified as target sites for this cleavage. Cleavage of RNF31 suppressed its ability to activate NF-kappa B signaling; thus, mutation of cleavage sites inhibited the induction of apoptosis by treatment with tumor necrosis factor alpha (TNF-alpha). Our findings elucidate a novel regulatory loop between cell death and the survival signal and may provide guidance for the development of therapeutic strategies for cancers through the sensitization of tumor cells to death-inducing drugs.