Roquin Represses Autoimmune Responses

Science's STKE  31 May 2005:
Vol. 2005, Issue 286, pp. tw205
DOI: 10.1126/stke.2862005tw205

When the mechanisms that ensure that the immune system does not attack self-antigens go awry, autoimmune disorders can occur. Vinuesa et al. screened the mouse genome for mutations that led to the production of ANAs (antibodies that recognize nuclear antigens), which are associated with autoimmune disorders such as lupus, and identified a strain of mice that developed ANAs within a few months of birth and had other features typical of lupus. The mice, which they called sanroque, exhibited increased abundance of a molecule known as inducible costimulatorymolecule (ICOS, a costimulatory receptor expressed on T cellsthat is required for B cell isotype switching and for T cell activation and function) and developed lymphadenopathy, enlarged spleens, and excess production of T cell-dependent immunoglobulin isotypes. Experiments with bone marrow chimeras containing wild-type and san/san hematopoietic cells indicated that the primary dysregulation was in T cells. Further, experiments in which mice were immunized with foreign antigen or engineered to express foreign antigen in pancreatic islets indicated that sanroque mice specifically lacked the ability to repress both self-reactive helper T cells and T cell help to self-reactive B cells. Sanroque mice had increased numbers of germinal centers and excess follicular helper T cells (a class of ICOS-expressing T cells associated with germinal centers). The mutation was mapped to a gene that the authors named roquin (rc3h1), which encoded a protein, Roquin, with an amino-terminal RING-1 zinc-finger domain characteristic of an E3 ubiquitin ligase and a CCCH zinc-finger domain found in RNA binding proteins. Roquin localized to cytoplasmic granules associated with regulation of mRNA translation and stability, and transduction of wild-type Roquin into sanroque T cells corrected ICOS overexpression. Thus, Roquin appears to suppress inappropriate immune response to self-antigens through a mechanism that may involve repression of ICOS expression.

C. G. Vinuesa, M. C. Cook, C. Angelucci, V. Athanasopoulos, L. Rui, K. M. Hill, D. Yu, H. Domaschenz, B. Whittle, T. Lambe, I. S. Roberts, R. R. Copley, J. I. Bell, R. J. Cornall, C. C. Goodnow, A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452-458 (2005). [PubMed]