SUMOylation is a post-translational modification (PTM) whereby members of the Small Ubiquitin-like MOdifier (SUMO) family of proteins are conjugated to lysine residues in target proteins. SUMOylation has been implicated in a wide range of physiological and pathological processes, and much attention has been given to its role in neurodegenerative conditions. Due to its reported role in neuroprotection, pharmacological modulation of SUMOylation represents an attractive potential therapeutic strategy in a number of different brain disorders. However, very few compounds that target the SUMOylation pathway have been identified. Guanosine is an endogenous nucleoside with important neuromodulatory and neuroprotective effects. Experimental evidence has shown that guanosine can modulate different intracellular pathways, including PTMs. In the present study we examined whether guanosine alters global protein SUMOylation. Primary cortical neurons and astrocytes were treated with guanosine at 1, 10, 100, 300, or 500 μM at four time points, 1, 6, 24, or 48 h. We show that guanosine increases global SUMO2/3-ylation in neurons and astrocytes at 1 h at concentrations above 10 μM. The molecular mechanisms involved in this effect were evaluated in neurons. The guanosine-induced increase in global SUMO2/3-ylation was still observed in the presence of dipyridamole, which prevents guanosine internalization, demonstrating an extracellular guanosine-induced effect. Furthermore, the A1 adenosine receptor antagonist DPCPX abolished the guanosine-induced increase in SUMO2/3-ylation. The A2A adenosine receptor antagonist ZM241385 increased SUMOylation per se, but did not alter guanosine-induced SUMOylation, suggesting that guanosine may modulate SUMO2/3-ylation through an A1-A2A receptor interaction. Taken together, this is the first report to show guanosine as a SUMO2/3-ylation enhancer in astrocytes and neurons.

SUMOylation 是一种翻译后修饰 (PTM)，通过这种修饰，Small Ubiquitin-like MOdifier (SUMO) 蛋白家族的成员与目标蛋白中的赖氨酸残基结合。SUMOylation 与广泛的生理和病理过程有关，并且它在神经退行性疾病中的作用受到了很多关注。由于其在神经保护中的作用，SUMOylation 的药理学调节代表了许多不同脑部疾病的有吸引力的潜在治疗策略。然而，很少有针对 SUMOylation 途径的化合物被鉴定出来。鸟苷是一种内源性核苷，具有重要的神经调节和神经保护作用。实验证据表明，鸟苷可以调节不同的细胞内途径，包括 PTM。在本研究中，我们检查了鸟苷是否会改变全局蛋白质 SUMO 化。在四个时间点（1、6、24 或 48 小时）用 1、10、100、300 或 500 μM 的鸟苷处理原代皮质神经元和星形胶质细胞。我们表明，鸟苷在 10 μM 以上的浓度下会在 1 小时内增加神经元和星形胶质细胞的整体 SUMO2/3-ylation。在神经元中评估了参与这种效应的分子机制。在双嘧达莫存在的情况下，仍然观察到鸟苷诱导的整体 SUMO2/3-ylation 增加，这阻止了鸟苷内化，证明了细胞外鸟苷诱导的作用。此外，A1 腺苷受体拮抗剂 DPCPX 消除了鸟苷诱导的 SUMO2/3-ylation 增加。A2A 腺苷受体拮抗剂 ZM241385 本身增加了 SUMOylation，但没有改变鸟苷诱导的 SUMOylation，表明鸟苷可能通过 A1-A2A 受体相互作用调节 SUMO2/3-ylation。综上所述，这是第一份将鸟苷作为星形胶质细胞和神经元中的 SUMO2/3-ylation 增强剂的报告。