Polyubiquitin binding to ABIN1 is required to prevent autoimmunity

Nanda, S.K., Venigalla, R.K.C., Ordureau, A., Patterson-Kane, J.C., Powell, D.W., Toth, R., C. Arthur, J.S. and Cohen, P. (2011) Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. Journal of Experimental Medicine, 208(6), pp. 1215-1228. (doi: 10.1084/jem.20102177)

Abstract

The protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor kappa B (NF-kappa B) essential modulator (NEMO), a component of the inhibitor of NF-kappa B (I kappa B) 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 p38 alpha 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Patterson-Kane, Professor Janet
• Authors: Nanda, S.K., Venigalla, R.K.C., Ordureau, A., Patterson-Kane, J.C., Powell, D.W., Toth, R., C. Arthur, J.S., and Cohen, P.
• Subjects: R Medicine > R Medicine (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Journal of Experimental Medicine
• Publisher: Rockefeller University Press
• ISSN: 0022-1007
• ISSN (Online): 1540-9538
• Published Online: 23 May 2011
• Copyright Holders: Copyright © 2011 The Authors
• First Published: First published in Journal of Experimental Medicine 208(6):1215-1228
• Publisher Policy: Reproduced with the permission of the authors