Polyubiquitin binding to ABIN1 is required to prevent autoimmunity

TY - JOUR

T1 - Polyubiquitin binding to ABIN1 is required to prevent autoimmunity

AU - Nanda, Sambit K.

AU - Venigalla, Ram K. C.

AU - Ordureau, Alban

AU - Patterson-Kane, Janet C.

AU - Powell, David W.

AU - Toth, Rachel

AU - Arthur, J. Simon C.

AU - Cohen, Philip

PY - 2011/6/6

Y1 - 2011/6/6

N2 - 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.

AB - 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.

KW - NF-KAPPA-B

KW - SYSTEMIC-LUPUS-ERYTHEMATOSUS

KW - CHINESE HAN POPULATION

KW - TOLL-LIKE-RECEPTORS

KW - T-CELLS

KW - LYS63-LINKED POLYUBIQUITINATION

KW - RHEUMATOID-ARTHRITIS

KW - KINASE TAK1

KW - ACTIVATION

KW - CHAINS

UR - https://www.scopus.com/pages/publications/79958281342

U2 - 10.1084/jem.20102177

DO - 10.1084/jem.20102177

M3 - Article

C2 - 21606507

SN - 0022-1007

VL - 208

SP - 1215

EP - 1228

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 6

ER -