Polyubiquitin binding to ABIN1 is required to prevent autoimmunity.
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Nanda SK, Venigalla RK, Ordureau A, Patterson-Kane JC, Powell DW, Toth R, Arthur JS, Cohen P
Polyubiquitin binding to ABIN1 is required to prevent autoimmunity.
J Exp Med. 2011 Jun 6;208(6):1215-28. doi: 10.1084/jem.20102177. Epub 2011 May 23.
- PubMed ID
- 21606507 [ View in PubMed]
- Abstract
The protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor kappaB (NF-kappaB) essential modulator (NEMO), a component of the inhibitor of NF-kappaB (IkappaB) 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-alpha/beta, c-Jun N-terminal kinases, and p38alpha 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.