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Type 1 diabetes mellitus (T1DM) is hallmarked by a complete loss of insulin secretion capacity caused by T cell-mediated destruction of pancreatic β-cells [1, 2]. The disorder has a complex pathogenesis involving genetic and environmental factors, it appears impossible hitherto to explain sufficiently how islet abnormalities arise and which mechanisms trigger immune cells to become diabetogenic. However, we already know that a series of immune-responsive mediators are involved in the occurrence of autoimmunity and the damage of β-cells; the most critical mediators are MHC class I and II molecules, cytotoxic enzymes and cytokines, such as interleukin-1β (IL-1β) and interferon-γ (IFN-γ) [3]. IL-1β and IFN-γ, which are potential mediators of islet inflammation and contributors of β-cell death [4], modify the expression of a number of genes in β-cells by themselves. But indirectly these mechanisms are regulated by transcriptional modifiers through pathways involving the nuclear transcription factor NF-κB [5], the activation of which is regarded as pro-apoptotic in pancreatic β-cells [6, 7]. Elevated activation of NF-κB has been shown to implicate the destruction of β-cells and the development of T1DM [8]. NF-κB was further demonstrated to be associated with T1DM [9, 10] and deficiency in this transcriptional regulator even prevents mice from streptozotocin-induced diabetes [11, 12]. One of the modifiers of NF-κB is a newly discovered post-transcriptional protein modifier which is, due to its functional and structural similarity with ubiquitin, called the small ubiquitin-like modifier (SUMO).  SUMO proteins control and modify a wide range of processes in eukaryotic cells including protein selection and stabilization. In particular, SUMO transfers ubiquitin-like proteins to target proteins by enzymatic cascades. This process of post-translational protein modification is termed sumoylation [13]. Sumoylation is a regulatory mechanism of protein function that involves signal transduction, glucose transport, tumor suppression and genome surveillance [14, 15]. The proteins that can be sumoylated also include IκBα, the NF-κB inhibitor, and the heat shock transcription factors HSF1 and HSF2. Four members of the SUMO family (SUMO1-4) have been identified to date. While SUMO1-3 have a wide tissue distribution, SUMO4 expression is restricted to immune tissues and kidney, making it a candidate mediator of autoimmune disorders such as T1DM [16, 17].

Is a New Immune Response Mediator in the NF-κB pathway - SUMO-4 - Related to Type 1 Diabetes?