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Mol Cell Biol. 2016 Nov 28;36(24):3010-3018. Print 2016 Dec 15.

Regulation of Linear Ubiquitin Chain Assembly Complex by Caspase-Mediated Cleavage of RNF31.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
2
Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China.
3
Department of Biochemistry and Molecular Biology, The University of Texas Medical School, Houston, Texas, USA.
4
Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA xllin@mdanderson.org.

Abstract

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-κB 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-κB signaling; thus, mutation of cleavage sites inhibited the induction of apoptosis by treatment with tumor necrosis factor alpha (TNF-α). 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.

PMID:
27669734
PMCID:
PMC5126289
DOI:
10.1128/MCB.00474-16
[Indexed for MEDLINE]
Free PMC Article

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