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 β 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 IκBα and inhibit NFκB transcriptional activity. The M55V substitution of SUMO4 may affect its ability to modify IκBα by sumoylation, and so lead to activation of NFκB 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 β cells and compared them with transgenic mice expressing a super-repressor of NFκB (a dominant negative form of NFκB, IκBαΔN) 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 IκBαΔN mice, mSUMO2 overexpression in T cells suppressed the production of both Th1 and Th2 cytokines. Whereas the mice overexpressing IκBαΔN 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 NFκB has pro-apoptotic activity, mSUMO2 plays a more complex role in the development of autoimmune diabetes. The relative influence of NFκB and sumoylation on the development of autoimmune diabetes in vivo may vary depending on the developmental stage and cell type.