Characterization of the regulatory roles of the SUMO

Abstract

Background Type 1 diabetes is a multi-factorial autoimmune disease that results from the destruction of insulin-producing beta cells of the pancreas; both genetic and environmental factors are thought to contribute to its development. Recently, a novel gene encoding small ubiquitin-like modifier protein 4 (SUMO4) was cloned and a single nucleotide substitution (M55V) was found to be strongly associated with type 1 diabetes. SUMO4 was shown to interact with I kappa B alpha and inhibit NF kappa B transcriptional activity. The M55V substitution of SUMO4 may affect its ability to modify I kappa B alpha by sumoylation, and so lead to activation of NF kappa B and transcription of genes implicated in the development of type 1 diabetes. However, the effects of sumoylation on immune cells are poorly understood. Methods Human SUMO1, 2, 3, 4 and mouse SUMO2 (mSUMO2) were cloned and overexpressed in dendritic, T and B cells using retroviral transduction. We then investigated whether SUMO overexpression affected their functions in vitro. To study the function of mSUMO2 in vivo, we made transgenic mice overexpressing mSUMO2 in T cells and pancreatic beta cells and compared them with transgenic mice expressing a super-repressor of NF kappa B (a dominant negative form of NF kappa B, I kappa B alpha Delta N) in T cells. Diabetes was induced in the two groups of mice by i.p. injection of streptozotocin. Results Human SUMO1, 2, 3, 4 and mSUMO2 were all found to negatively regulate the transcriptional activity of T, B and dendritic cells. Although mSUMO2 overexpression in dendritic cells did not alter the expression of major histocompatibility complex class II proteins or B7, IL-1, IL-6 and IL-7, IL-12 expression decreased, switching Th1-directed immune responses into Th2 responses. Unlike T cells from the I kappa B alpha Delta N mice, mSUMO2 overexpression in T cells suppressed the production of both Th1 and Th2 cytokines. Whereas the mice overexpressing I kappa B alpha Delta N were completely protected against diabetes, those expressing mSUMO2 had the same susceptibility to diabetes as wild type. Conclusion These results indicate that at least in T cells, whereas NF kappa B has pro-apoptotic activity, mSUMO2 plays a more complex role in the development of autoimmune diabetes. The relative influence of NF kappa B and sumoylation on the development of autoimmune diabetes in vivo may vary depending on the developmental stage and cell type. Copyright (C) 2011 John Wiley & Sons, Ltd.