Polyubiquitin binding to ABIN1 is required to prevent autoimmunity

• DOI: 10.1084/jem.20102177
• Publication Date: 2011-05-24T05:00:15Z
• Authors: Sambit K. Nanda; Ram K.C. Venigalla; Alban Ordureau; Janet C. Patterso...; David W. Powell; Rachel Toth; J. Simon C. Arthur; Philip Cohen
• Keywords: IκB kinase; Isotype; Protein kinase domain

The protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor κB (NF-κB) essential modulator (NEMO), component of the inhibitor NF-κB (IκB) kinase (IKK) complex. To address physiological significance polyubiquitin binding, we generated knockin mice expressing ABIN1[D485N] mutant instead wild-type (WT) protein. These developed all hallmarks autoimmunity, including spontaneous formation germinal centers, isotype switching, and production autoreactive antibodies. Autoimmunity was suppressed by crossing MyD88−/− mice, demonstrating toll-like receptor (TLR)–MyD88 signaling pathways are needed for phenotype develop. B cells myeloid showed enhanced activation kinases TAK, IKK-α/β, c-Jun N-terminal kinases, p38α mitogen-activated produced more IL-6 IL-12 than WT. also proliferated rapidly response TLR ligands. Our results indicate interaction with is required limit TLR–MyD88 prevent autoimmunity.