Abstract
Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sanroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability.
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Acknowledgements
We thank the staff of the Australian Phenomics Facility for care, breeding and phenotyping of mice; A. Prins for histology; D. Webb for help with cytokine ELISAs; E. Kucharska for help with immunizations; and A. Murtagh and D. Buckle for help with sequencing. The work was supported by grants from the Wellcome Trust (UK), the Juvenile Diabetes Research Foundation, the National Health and Medical Research Council, and the National Institutes of Health. C.G.V. was the recipient of a Wellcome Trust International Prize Travelling Fellowship.
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The mouse Roquin sequence has been deposited in GenBank under accession number AY948287. The gene symbols assigned by the mouse and human genome nomenclature committees are Rc3h1 and RC3H1, respectively. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Supplementary information
Supplementary Figures S1-S12
This file contains 12 Supplementary Figures that provide detailed characterization of the incidence, female:male bias and gene dose effects of the sanroque phenotype including ANAs, Ig titres, glomerulonephritis, flow cytometric analysis of all lymphoid compartments, immunohistology of splenic germinal centres, response to immunization and known tolerance pathways. Mapping and genotyping details of the sanroque mutation and Roquin mRNA expression are also provided, together with the full Roquin preotein sequence and phylogenetic conservation. (PDF 921 kb)
Supplementary Figures Legends
This file contains a brief description for each of the 12 Supplementary Figures. (DOC 49 kb)
Supplementary Methods
Details of the Supplementary Methods used for Flow cytometry, CFSE labelling, and immunohistology. (DOC 25 kb)
Supplementary Data
This file contains the microarray data referred to in the paper in MIAME-compliant format and a completed MIAME checklist. (XLS 14340 kb)
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Vinuesa, C., Cook, M., Angelucci, C. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005). https://doi.org/10.1038/nature03555
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DOI: https://doi.org/10.1038/nature03555
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