Targeted DeSUMOylation as a therapeutic strategy for multiple sclerosis.

ABSTRACT

SUMO (small ubiquitin like modifier) conjugated proteins have emerged as an important post translational modifier of cellular function. SUMOylation modulates several cellular processes involved in transcriptional regulation of genes, protein-protein interactions and DNA damage and repair. Since abnormalities in SUMOylation has been observed in neoplastic and neurodegenerative disorders, the SUMO pathway has become an attractive site for targeting of new therapies to regulate SUMOylation and reduce disease burden. Conjugation of SUMO to their respective substrates is orchestrated by an enzymatic cascade involving three main enzymes, E1, activation enzyme, E2, conjugating enzyme and E3, a protein ligase. Each of these enzymes are therefore potential "druggable" sites for future therapeutics. SUMOylation is a well-known mechanism by which the innate immune response is regulated in response to viral infections and in the adaptive immune response to tumor immunity. We have shown that small molecules which inhibit the SUMO activation pathway are also capable of inhibiting autoimmune response. TAK981 which forms adducts with SUMO and anacardic acid which inhibits the E1 enzyme of the SUMO pathway were effective in preventing the development of experimental allergic encephalitis (EAE), a mouse model of multiple sclerosis. Anacardic acid and TAK981 inhibited activation of TH17 cells and reduced clinical and pathological injury in IL-17 mediated myelin oligodendrocyte glycoprotein (MOG) induced EAE. Ginkgolic acid, another known inhibitor of SUMO pathway, was also shown to be effective in reducing the severity of inflammatory arthropathies which is also IL-17 mediated. In addition, the increase in the transcription of myelin genes with TAK981 and anacardic acid improved remyelination in experimental models of demyelination. In the present review paper, we examine the mechanism of action of inhibitors of the SUMO pathway on regulating the immune response and the possibility of the use of these agents as therapeutics for MS.