SUMOylation in brain ischemia: Patterns, targets, and translational implications

Abstract

Post-translational protein modification by small ubiquitin-like modifier (SUMO) regulates a myriad of homeostatic and stress responses. The SUMOylation pathway has been extensively studied in brain ischemia. Convincing evidence is now at hand to support the notion that a major increase in levels of SUMOylated proteins is capable of inducing tolerance to ischemic stress. Therefore, the SUMOylation pathway has emerged as a promising therapeutic target for neuroprotection in the face of brain ischemia. Despite this, it is prudent to acknowledge that there are many key questions still to be addressed in brain ischemia related to SUMOylation. Accordingly, herein, we provide a critical review of literature within the field to summarize current knowledge and in so doing highlight pertinent translational implications of the SUMOylation pathway in brain ischemia.

Keywords: Brain ischemia; SUMOylation; cell-therapy; drug repurposing; hypothermia; neuroprotection; stroke.

Figure 1.

SUMO conjugation-deconjugation cycling, known modulators thereof, and functional consequences of SUMOylation. Maturation of the SUMO precursors is catalyzed by the endopeptidase activity of SENPs, which exposes a GG motif. In the activation step, the SAE1/SAE2 heterodimeric E1 enzyme binds to SUMO in an ATP-dependent process forming a thioester bond (red). A number of compounds have been identified as modulators of the activation step: N106 is an activator, while kerriamycin B1, gingkolic acid, anacardic acid, miRNA-182, and davidiin are inhibitors. SUMO is then transferred to the E2 ligase Ubc9. Ubc9 is inhibited by miRNAs 182 and 183, 2-D08, and spectomycin B1. Critically, inhibition of miRNAs 182 and 183 is neuroprotective in cell culture. With the assistance of a substrate-specific E3 protein, Ubc9 targets SUMO to a substrate protein, conjugates it to the target’s ɛ-amino-group lysine, thereby forming an isopeptide bond (blue). SUMO is deconjugated via the isopeptidase activity of SENPs, which may be inhibited by small molecules such as quercetin to effect neuroprotection. SUMOylation may regulate target protein stability/degradation through interactions with ubiquitin (e.g. blocking the ubiquitination site or recruiting STUbLs), induce conformational changes and thus functional alterations in target proteins, or promote or inhibit interactions between the target protein and other proteins.