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CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death : so similar, yet so different

Marie Lork (UGent) , Kelly Verhelst (UGent) and Rudi Beyaert (UGent)
(2017) CELL DEATH AND DIFFERENTIATION. 24(7). p.1172-1183
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Abstract
Polyubiquitination of proteins has a pivotal role in the regulation of numerous cellular functions such as protein degradation, DNA repair and cell signaling. As deregulation of these processes can result in pathological conditions such as inflammatory diseases, neurodegeneration or cancer, tight regulation of the ubiquitin system is of tremendous importance. Ubiquitination by E3 ubiquitin ligases can be counteracted by the activity of several deubiquitinating enzymes (DUBs). CYLD, A20 and OTULIN have been implicated as key DUBs in the negative regulation of NF-kappa B transcription factor-mediated gene expression upon stimulation of cytokine receptors, antigen receptors and pattern recognition receptors, by removing distinct types of polyubiquitin chains from specific NF-kappa B signaling proteins. In addition, they control TNF-induced cell death signaling leading to apoptosis and necroptosis via similar mechanisms. In the case of A20, also catalytic-independent mechanisms of action have been demonstrated to have an important role. CYLD, A20 and OTULIN have largely overlapping substrates, suggesting at least partially redundant functions. However, mice deficient in one of the three DUBs show significant phenotypic differences, indicating also non-redundant functions. Here we discuss the activity and polyubiquitin chain-type specificity of CYLD, A20 and OTULIN, their specific role in NF-kappa B signaling and cell death, the molecular mechanisms that regulate their activity, their role in immune homeostasis and the association of defects in their activity with inflammation, autoimmunity and cancer.
Keywords
TUMOR-SUPPRESSOR CYLD, EDITING ENZYME A20, ZINC-FINGER PROTEIN, ONSET, AUTOINFLAMMATORY DISEASE, ACUTE LYMPHOBLASTIC-LEUKEMIA, LINEAR, POLYUBIQUITIN CHAINS, ALPHA-INDUCED APOPTOSIS, INDUCED JNK ACTIVATION, SPATA2 LINKS CYLD, E3 LIGASE ITCH

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Citation

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Chicago
Lork, Marie, Kelly Verhelst, and Rudi Beyaert. 2017. “CYLD, A20 and OTULIN Deubiquitinases in NF-κB Signaling and Cell Death : so Similar, yet so Different.” Cell Death and Differentiation 24 (7): 1172–1183.
APA
Lork, M., Verhelst, K., & Beyaert, R. (2017). CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death : so similar, yet so different. CELL DEATH AND DIFFERENTIATION, 24(7), 1172–1183.
Vancouver
1.
Lork M, Verhelst K, Beyaert R. CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death : so similar, yet so different. CELL DEATH AND DIFFERENTIATION. 2017;24(7):1172–83.
MLA
Lork, Marie, Kelly Verhelst, and Rudi Beyaert. “CYLD, A20 and OTULIN Deubiquitinases in NF-κB Signaling and Cell Death : so Similar, yet so Different.” CELL DEATH AND DIFFERENTIATION 24.7 (2017): 1172–1183. Print.
@article{8527472,
  abstract     = {Polyubiquitination of proteins has a pivotal role in the regulation of numerous cellular functions such as protein degradation, DNA repair and cell signaling. As deregulation of these processes can result in pathological conditions such as inflammatory diseases, neurodegeneration or cancer, tight regulation of the ubiquitin system is of tremendous importance. Ubiquitination by E3 ubiquitin ligases can be counteracted by the activity of several deubiquitinating enzymes (DUBs). CYLD, A20 and OTULIN have been implicated as key DUBs in the negative regulation of NF-kappa B transcription factor-mediated gene expression upon stimulation of cytokine receptors, antigen receptors and pattern recognition receptors, by removing distinct types of polyubiquitin chains from specific NF-kappa B signaling proteins. In addition, they control TNF-induced cell death signaling leading to apoptosis and necroptosis via similar mechanisms. In the case of A20, also catalytic-independent mechanisms of action have been demonstrated to have an important role. CYLD, A20 and OTULIN have largely overlapping substrates, suggesting at least partially redundant functions. However, mice deficient in one of the three DUBs show significant phenotypic differences, indicating also non-redundant functions. Here we discuss the activity and polyubiquitin chain-type specificity of CYLD, A20 and OTULIN, their specific role in NF-kappa B signaling and cell death, the molecular mechanisms that regulate their activity, their role in immune homeostasis and the association of defects in their activity with inflammation, autoimmunity and cancer.},
  author       = {Lork, Marie and Verhelst, Kelly and Beyaert, Rudi},
  issn         = {1350-9047},
  journal      = {CELL DEATH AND DIFFERENTIATION},
  keywords     = {TUMOR-SUPPRESSOR CYLD,EDITING ENZYME A20,ZINC-FINGER PROTEIN,ONSET,AUTOINFLAMMATORY DISEASE,ACUTE LYMPHOBLASTIC-LEUKEMIA,LINEAR,POLYUBIQUITIN CHAINS,ALPHA-INDUCED APOPTOSIS,INDUCED JNK ACTIVATION,SPATA2 LINKS CYLD,E3 LIGASE ITCH},
  language     = {eng},
  number       = {7},
  pages        = {1172--1183},
  title        = {CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death : so similar, yet so different},
  url          = {http://dx.doi.org/10.1038/cdd.2017.46},
  volume       = {24},
  year         = {2017},
}

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