Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy.
CEINGE Biotecnologie Avanzate and Department of Chemical Science, University of Naples "Federico II, Naples, Italy.
Free Radic Biol Med. 2018 Mar;117:191-201. doi: 10.1016/j.freeradbiomed.2018.02.005. Epub 2018 Feb 8.
STAT1 and STAT3 are two transcription factors involved in a lot of cellular functions such as immune response, proliferation, apoptosis, and cell survival. A number of literature evidences described a yin-yang relationship between activation of STAT1 and STAT3 in neurodegenerative disorders where STAT1 exerts a pro-apoptotic effect whereas STAT3 shows neuroprotective properties through the inhibition of apoptosis. Although the role of oxidative-stress in the pathogenesis of neurodegeneration is clearly described, its influence in the regulation of these pathways is poorly understood. Herein, we demonstrate that HO rapidly induces phosphorylation of STAT1 whereas it is not able to influence phosphorylation of STAT3 in mouse microglia BV2 cells. The analysis of the molecular mechanism of STATs signaling reveals that HO induces S-glutathionylation of both STAT1 and STAT3. The same post-translational event exerts an opposing role in the regulation of STAT1 and STAT3 signaling. These data not only confirm redox sensibility of STAT3 signaling but also reveal for the first time that STAT1 is susceptible to redox regulation. A deep study of the molecular mechanism of STAT1 redox regulation, identifies Cys324 and Cys492 as the main targets of S-glutathionylation and confirms that S-glutathionylation does not impair JAK2 mediated STAT1 tyrosine phosphorylation. These results demonstrate that both phosphorylation and glutathionylation contribute to activation of STAT1 during oxidative stress and underline that the same post-translation event exerts an opposing role in the regulation of STAT1 and STAT3 signaling in microglia cells.
STAT1 和 STAT3 是两种转录因子，参与许多细胞功能，如免疫反应、增殖、凋亡和细胞存活。大量文献证据描述了 STAT1 和 STAT3 在神经退行性疾病中的激活之间存在一种阴阳关系，其中 STAT1 发挥促凋亡作用，而 STAT3 通过抑制细胞凋亡表现出神经保护特性。尽管氧化应激在神经变性发病机制中的作用已被清楚描述，但它对这些途径的调节影响知之甚少。在此，我们证明 HO 可迅速诱导 STAT1 的磷酸化，而不能影响 STAT3 在小鼠小胶质细胞 BV2 细胞中的磷酸化。对 STATs 信号转导的分子机制的分析表明，HO 诱导 STAT1 和 STAT3 的 S-谷胱甘肽化。这种翻译后修饰事件在调节 STAT1 和 STAT3 信号转导中发挥相反的作用。这些数据不仅证实了 STAT3 信号转导的氧化还原敏感性，而且还首次揭示了 STAT1 易受氧化还原调节。对 STAT1 氧化还原调节的分子机制的深入研究确定了 Cys324 和 Cys492 作为 S-谷胱甘肽化的主要靶标，并证实 S-谷胱甘肽化不会损害 JAK2 介导的 STAT1 酪氨酸磷酸化。这些结果表明，在氧化应激过程中，磷酸化和谷胱甘肽化均有助于 STAT1 的激活，并强调同一翻译后修饰事件在调节小胶质细胞中 STAT1 和 STAT3 信号转导中发挥相反的作用。
