Advanced search
1 file | 7.78 MB Add to list

Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities

Arne Martens (UGent) , Dario Priem (UGent) , Esther Hoste (UGent) , Jessica Vetters (UGent) , Sofie Rennen (UGent) , Leen Catrysse (UGent) , Sofie Voet (UGent) , Laura Deelen (UGent) , Mozes Sze (UGent) , Hanna-Kaisa Vikkula (UGent) , et al.
(2020) NATURE IMMUNOLOGY. 21(4). p.381-387
Author
Organization
Abstract
Protein ubiquitination regulates protein stability and modulates the composition of signaling complexes. A20 is a negative regulator of inflammatory signaling, but the molecular mechanisms involved are ill understood. Here, we generated Tnfaip3 gene-targeted A20 mutant mice bearing inactivating mutations in the zinc finger 7 (ZnF7) and ZnF4 ubiquitin-binding domains, revealing that binding to polyubiquitin is essential for A20 to suppress inflammatory disease. We demonstrate that a functional ZnF7 domain was required for recruiting A20 to the tumor necrosis factor receptor 1 (TNFR1) signaling complex and to suppress inflammatory signaling and cell death. The combined inactivation of ZnF4 and ZnF7 phenocopied the postnatal lethality and severe multiorgan inflammation of A20-deficient mice. Conditional tissue-specific expression of mutant A20 further revealed the key role of ubiquitin-binding in myeloid and intestinal epithelial cells. Collectively, these results demonstrate that the anti-inflammatory and cytoprotective functions of A20 are largely dependent on its ubiquitin-binding properties. van Loo and colleagues provide insights into the action of the anti-inflammatory protein A20. The ZnF7 and ZnF4 ubiquitin-binding domains of A20 are both required to suppress inflammatory signaling and cell death; however, these zinc fingers operate via distinct mechanisms.
Keywords
NF-KAPPA-B, LINEAR POLYUBIQUITIN, TNFAIP3, GENE, INFLAMMATION, DEFICIENCY, ACTIVATION, MUTATIONS, DOMAINS, DEATH

Downloads

  • (...).pdf
    • full text (Published version)
    • |
    • UGent only
    • |
    • PDF
    • |
    • 7.78 MB

Citation

Please use this url to cite or link to this publication:

MLA
Martens, Arne, et al. “Two Distinct Ubiquitin-Binding Motifs in A20 Mediate Its Anti-Inflammatory and Cell-Protective Activities.” NATURE IMMUNOLOGY, vol. 21, no. 4, 2020, pp. 381–87.
APA
Martens, A., Priem, D., Hoste, E., Vetters, J., Rennen, S., Catrysse, L., … van Loo, G. (2020). Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities. NATURE IMMUNOLOGY, 21(4), 381–387.
Chicago author-date
Martens, Arne, Dario Priem, Esther Hoste, Jessica Vetters, Sofie Rennen, Leen Catrysse, Sofie Voet, et al. 2020. “Two Distinct Ubiquitin-Binding Motifs in A20 Mediate Its Anti-Inflammatory and Cell-Protective Activities.” NATURE IMMUNOLOGY 21 (4): 381–87.
Chicago author-date (all authors)
Martens, Arne, Dario Priem, Esther Hoste, Jessica Vetters, Sofie Rennen, Leen Catrysse, Sofie Voet, Laura Deelen, Mozes Sze, Hanna-Kaisa Vikkula, Karolina Slowicka, Tino Hochepied, Kalliopi Iliaki, Andy Wullaert, Sophie Janssens, Mohamed Lamkanfi, Rudi Beyaert, Marietta Armaka, Mathieu Bertrand, and Geert van Loo. 2020. “Two Distinct Ubiquitin-Binding Motifs in A20 Mediate Its Anti-Inflammatory and Cell-Protective Activities.” NATURE IMMUNOLOGY 21 (4): 381–387.
Vancouver
1.
Martens A, Priem D, Hoste E, Vetters J, Rennen S, Catrysse L, et al. Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities. NATURE IMMUNOLOGY. 2020;21(4):381–7.
IEEE
[1]
A. Martens et al., “Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities,” NATURE IMMUNOLOGY, vol. 21, no. 4, pp. 381–387, 2020.
@article{8660955,
  abstract     = {Protein ubiquitination regulates protein stability and modulates the composition of signaling complexes. A20 is a negative regulator of inflammatory signaling, but the molecular mechanisms involved are ill understood. Here, we generated Tnfaip3 gene-targeted A20 mutant mice bearing inactivating mutations in the zinc finger 7 (ZnF7) and ZnF4 ubiquitin-binding domains, revealing that binding to polyubiquitin is essential for A20 to suppress inflammatory disease. We demonstrate that a functional ZnF7 domain was required for recruiting A20 to the tumor necrosis factor receptor 1 (TNFR1) signaling complex and to suppress inflammatory signaling and cell death. The combined inactivation of ZnF4 and ZnF7 phenocopied the postnatal lethality and severe multiorgan inflammation of A20-deficient mice. Conditional tissue-specific expression of mutant A20 further revealed the key role of ubiquitin-binding in myeloid and intestinal epithelial cells. Collectively, these results demonstrate that the anti-inflammatory and cytoprotective functions of A20 are largely dependent on its ubiquitin-binding properties. van Loo and colleagues provide insights into the action of the anti-inflammatory protein A20. The ZnF7 and ZnF4 ubiquitin-binding domains of A20 are both required to suppress inflammatory signaling and cell death; however, these zinc fingers operate via distinct mechanisms.},
  author       = {Martens, Arne and Priem, Dario and Hoste, Esther and Vetters, Jessica and Rennen, Sofie and Catrysse, Leen and Voet, Sofie and Deelen, Laura and Sze, Mozes and Vikkula, Hanna-Kaisa and Slowicka, Karolina and Hochepied, Tino and Iliaki, Kalliopi and Wullaert, Andy and Janssens, Sophie and Lamkanfi, Mohamed and Beyaert, Rudi and Armaka, Marietta and Bertrand, Mathieu and van Loo, Geert},
  issn         = {1529-2908},
  journal      = {NATURE IMMUNOLOGY},
  keywords     = {NF-KAPPA-B,LINEAR POLYUBIQUITIN,TNFAIP3,GENE,INFLAMMATION,DEFICIENCY,ACTIVATION,MUTATIONS,DOMAINS,DEATH},
  language     = {eng},
  number       = {4},
  pages        = {381--387},
  title        = {Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities},
  url          = {http://dx.doi.org/10.1038/s41590-020-0621-9},
  volume       = {21},
  year         = {2020},
}

Altmetric
View in Altmetric
Web of Science
Times cited: