Polyubiquitin binding to ABIN1 is required to prevent autoimmunity
| Autor: | Rachel Toth, Janet C. Patterson-Kane, Alban Ordureau, David W. Powell, Philip Cohen, Sambit K. Nanda, Ram K C Venigalla, J. Simon C. Arthur |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Immunology Autoimmunity Mice Transgenic macromolecular substances IκB kinase Biology Ligands environment and public health Article Mitogen-Activated Protein Kinase 14 Mice 03 medical and health sciences 0302 clinical medicine Animals Humans Immunology and Allergy Polyubiquitin Protein kinase A Adaptor Proteins Signal Transducing 030304 developmental biology 0303 health sciences Kinase Lysine NF-kappa B I-Kappa-B Kinase Germinal center Molecular biology I-kappa B Kinase 3. Good health DNA-Binding Proteins Mutation Myeloid Differentiation Factor 88 Cytokines Female Signal transduction Polyubiquitin binding Signal Transduction 030215 immunology |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | The polyubiquitin-binding domain of ABIN1 limits TLR-induced MyD88 signaling to prevent spontaneous autoimmunity in mice. The protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor κB (NF-κB) essential modulator (NEMO), a component of the inhibitor of NF-κB (IκB) kinase (IKK) complex. To address the physiological significance of polyubiquitin binding, we generated knockin mice expressing the ABIN1[D485N] mutant instead of the wild-type (WT) protein. These mice developed all the hallmarks of autoimmunity, including spontaneous formation of germinal centers, isotype switching, and production of autoreactive antibodies. Autoimmunity was suppressed by crossing to MyD88−/− mice, demonstrating that toll-like receptor (TLR)–MyD88 signaling pathways are needed for the phenotype to develop. The B cells and myeloid cells of the ABIN1[D485N] mice showed enhanced activation of the protein kinases TAK, IKK-α/β, c-Jun N-terminal kinases, and p38α mitogen-activated protein kinase and produced more IL-6 and IL-12 than WT. The mutant B cells also proliferated more rapidly in response to TLR ligands. Our results indicate that the interaction of ABIN1 with polyubiquitin is required to limit the activation of TLR–MyD88 pathways and prevent autoimmunity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|