Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, 060-8638, Japan.
Department of Food and Health Sciences, International College of Arts and Sciences, Fukuoka Women's University, Fukuoka, 813-8582, Japan.
Biochem Biophys Res Commun. 2022 Oct 15;625:94-101. doi: 10.1016/j.bbrc.2022.08.003. Epub 2022 Aug 5.
The expression of the ubiquitin-like molecule interferon-stimulated gene 15 kDa (ISG15) and post-translational protein modification by ISG15 (ISGylation) are strongly activated by interferons or pathogen infection, suggesting that ISG15 and ISGylation play an important role in innate immune responses. More than 400 proteins have been found to be ISGylated. ISG15 is removed from substrates by interferon-induced ubiquitin-specific peptidase 18 or severe acute respiratory syndrome coronavirus 2‒derived papain-like protease. Therefore, maintaining strong ISGylation may help prevent the spread of coronavirus disease 2019 (COVID-19). However, it is unknown whether nutrients or chemicals affect ISGylation level. Curcumin is the major constituent of turmeric and functions as an immunomodulator. Here, we investigated the effect of curcumin on ISGylation. MCF10A and A549 cells were treated with interferon α and curcumin after which the expression levels of various proteins were determined. The effect of curcumin on ubiquitylation was also determined. Curcumin treatment was found to reduce ISGylation in a dose-dependent manner. The findings suggested that curcumin partly prevents disulfide bond-mediated ISG15 dimerization directly or indirectly, thereby increasing monomer ISG15 levels. Reduced ISGylation may also occur via the prevention of ISG15 activation by ubiquitin-activating enzyme E1-like protein. In conclusion, curcumin treatment was found to reduce ISGylation, suggesting that it may contribute to severe COVID-19. This is the first study to report a relationship between ISGylation and a food component.
干扰素刺激基因 15kDa（ISG15）的泛素样分子表达和 ISG15 的翻译后蛋白修饰（ISGylation）在干扰素或病原体感染下强烈激活，这表明 ISG15 和 ISGylation 在先天免疫反应中发挥着重要作用。已经发现超过 400 种蛋白质被 ISGylation。干扰素诱导的泛素特异性肽酶 18 或严重急性呼吸综合征冠状病毒 2 衍生的木瓜蛋白酶样蛋白酶将 ISG15 从底物中去除。因此，保持强烈的 ISGylation 可能有助于阻止 2019 年冠状病毒病（COVID-19）的传播。然而，目前尚不清楚营养素或化学物质是否会影响 ISGylation 水平。姜黄素是姜黄的主要成分，具有免疫调节剂的作用。在这里，我们研究了姜黄素对 ISGylation 的影响。用干扰素 α 和姜黄素处理 MCF10A 和 A549 细胞，然后测定各种蛋白质的表达水平。还测定了姜黄素对泛素化的影响。结果发现，姜黄素处理以剂量依赖性方式降低 ISGylation。研究结果表明，姜黄素可能直接或间接地部分阻止二硫键介导的 ISG15 二聚化，从而增加单体 ISG15 水平。ISGylation 的减少也可能通过防止泛素激活酶 E1 样蛋白对 ISG15 的激活来发生。总之，姜黄素处理被发现降低了 ISGylation，这表明它可能导致严重的 COVID-19。这是第一项报道 ISGylation 与食物成分之间关系的研究。
