Regulation of Linear Ubiquitin Chain Assembly Complex by Caspase-Mediated Cleavage of RNF31.
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.
Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Donghyun
D
Joo
Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China.
Yong
Y
Tang
Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Marzenna
M
Blonska
Department of Biochemistry and Molecular Biology, The University of Texas Medical School, Houston, Texas, USA.
Jianping
J
Jin
Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China.
Xueqiang
X
Zhao
Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA xllin@mdanderson.org.|Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China.
Xin
X
Lin
D000072283:A549 Cells; D017209:Apoptosis / Q000187:drug effects; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D053178:Caspase 6 / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D001224:Aspartic Acid; D043743:Ubiquitin-Protein Ligase Complexes; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases; C505407:CASP3 protein, human; C505514:CASP6 protein, human; D053148:Caspase 3; D053178:Caspase 6
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