engleski

In vitro SUMOylation of proteins involved in mental illness

Post-translational modifications have long been implicated in a range of diseases, including chronic mental illnesses. SUMOylation is a reversible, covalent post-translational modification that involves attachment of small ubiquitin-related modifiers (SUMOs) to lysine residues of its numerous target proteins. It has a role in a wide array of cellular processes, including, but not limited to brain development, synapse formation and neuronal maturation. Disrupted in Schizophrenia 1 (DISC1) is a known SUMOylation target. It is encoded by the DISC1 gene, a major risk factor in numerous mental illnesses including schizophrenia, bipolar disorder and major depression. However, the mechanism by which it is regulated is still largely unknown, partly due to a lack of knowledge of the structure of DISC1. Recently, four novel DISC1 regions labelled “D”, “I”, “S” and “C” have been discovered. Here, we set out to confirm DISC1 SUMOylation in vitro, taking its recently discovered domain structure into consideration. Furthermore, we investigated two additional SUMOylation targets, TRIO F-actin-binding protein 1 (TRIOBP-1) and dysbindin 1A, both of which are implicated in pathology of mental illnesses. We used a recombinant SUMOylation assay to express novel DISC1 regions containing the previously reported SUMOylation site at lysine residue 643 (K643). Furthermore, we employed in silico methods to predict possible SUMOylation sites in TRIOBP-1 and dysbindin 1A, then tested them in vitro. In this study, we suggest in vitro DISC1 SUMOylation of K643 within the “S” region. However, our data also implicates the existence of another SUMOylation site within the DISC1 sequence. Furthermore, our results suggest that TRIOBP-1 is also prone to SUMOylation, which is, to our knowledge, the first report of such occurrence. We also report negative results on the SUMOylation of dysbindin 1A. Altogether, these results present a solid base for future research of the involvement of SUMOylation in the pathology of mental illnesses.

mental illness ; SUMOylation ; DISC1 ; TRIOBP-1 ; dysbindin 1A

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