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Polyubiquitin binding to ABIN1 is required to prevent autoimmunity
Sambit K Nanda1, Ram K C Venigalla, Alban Ordureau
1Medical Research Council Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK. s.k.nanda@dundee.ac.uk
The Journal of Experimental Medicine
|May 25, 2011
Summary
The protein ABIN1 normally prevents autoimmunity by regulating Toll-like receptor (TLR) signaling. Disrupting ABIN1
Area of Science:
- Immunology
- Molecular Biology
Background:
- ABIN1 protein has a polyubiquitin-binding domain similar to NEMO, a component of the IKK complex.
- The physiological role of ABIN1's polyubiquitin binding in regulating immune responses is not fully understood.
Purpose of the Study:
- To investigate the physiological significance of ABIN1's polyubiquitin-binding activity in vivo.
- To determine the role of ABIN1 in regulating Toll-like receptor (TLR) signaling pathways and preventing autoimmunity.
Main Methods:
- Generation of knockin mice expressing a mutant ABIN1 (ABIN1[D485N]) lacking polyubiquitin-binding ability.
- Analysis of autoimmune phenotypes in mutant mice, including germinal center formation, isotype switching, and autoantibody production.
- Investigating the involvement of TLR-MyD88 signaling by crossing mutant mice with MyD88(-/-) mice.
- Assessing immune cell activation, cytokine production (IL-6, IL-12), and proliferation in response to TLR ligands.
Main Results:
- ABIN1[D485N] mice exhibited spontaneous autoimmunity, characterized by germinal centers, isotype switching, and autoantibodies.
- Autoimmunity in these mice was dependent on TLR-MyD88 signaling, as it was suppressed in MyD88(-/-) double mutants.
- Mutant B cells and myeloid cells showed enhanced activation of kinases (TAK, IKK-α/β, JNKs, p38 MAPK) and increased production of IL-6 and IL-12.
- Mutant B cells displayed increased proliferation upon stimulation with TLR ligands.
Conclusions:
- ABIN1's interaction with polyubiquitin is crucial for limiting TLR-MyD88 pathway activation.
- This interaction is essential for preventing the development of autoimmunity.
- ABIN1 acts as a negative regulator of TLR signaling, maintaining immune homeostasis.
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