Nitrosylation of ISG15 prevents the disulfide bond-mediated dimerization of ISG15 and contributes to effective ISGylation
Nitrosylation of ISG15 prevents the disulfide bond-mediated dimerization of ISG15 and contributes to effective ISGylation
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DOI：
10.1074/jbc.m803795200
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发表时间：
2008-09-05
影响因子：
4.8
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
--
作者：
Okumura, Fumihiko;Lenschow, Deborah J.;Zhang, Dong-Er
泛素样分子ISG15(UCRP)的表达和ISG15的蛋白修饰(ISG化)被干扰素、基因毒性应激和病原体感染强烈激活，提示ISG15在先天性免疫反应中发挥重要作用。诱导型一氧化氮合酶(INOS)是由类似于ISG15的刺激诱导的，它能促进一氧化氮(NO)的产生，一氧化氮是一种具有抗病原体活性的多效性自由基。在这里，我们报道了ISG15的半胱氨酸残基(小鼠的Cys-76和-143，人的Cys-78)可以被NO修饰，并且ISG15的NO修饰减少了ISG15的二聚化。ISG15的半胱氨酸残基突变为丝氨酸，提高了总ISG化水平。一氧化氮合酶抑制剂S-乙基异硫脲减少内源性ISG化。此外，诱导型一氧化氮合酶的异位表达增强了总ISG化。综上所述，这些结果表明ISG15的亚硝化增强了目标蛋白的ISG化。这是关于ISG化和亚硝化之间关系的第一个报道。
The expression of the ubiquitin-like molecule ISG15 (UCRP) and protein modification by ISG15 (ISGylation) are strongly activated by interferon, genotoxic stress, and pathogen infection, suggesting that ISG15 plays an important role in innate immune responses. Inducible nitric-oxide synthase (iNOS) is induced by the similar stimuli as ISG15 and enhances the production of nitric oxide (NO), a pleiotropic free radical with anti-pathogen activity. Here, we report that cysteine residues (Cys-76 and -143 in mouse, Cys-78 in human) of ISG15 can be modified by NO, and the NO modification of ISG15 decreases the dimerization of ISG15. The mutation of the cysteine residue of ISG15 to serine improves total ISGylation. The NO synthase inhibitor S-ethylisothiourea reduces endogenous ISGylation. Furthermore, ectopic expression of iNOS enhanced total ISGylation. Together, these results suggest that nitrosylation of ISG15 enhances target protein ISGylation. This is the first report of a relationship between ISGylation and nitrosylation.