Section of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
Mol Cell. 2010 Jun 11;38(5):722-32. doi: 10.1016/j.molcel.2010.05.002.
ISG15 is an interferon-induced and antiviral ubiquitin-like protein (Ubl). Herc5, the major E3 enzyme for ISG15, mediates the ISGylation of more than 300 proteins in interferon-stimulated cells. In addressing this broad substrate selectivity of Herc5, we found that: (1) the range of substrates extends even further and includes many exogenously expressed foreign proteins, (2) ISG15 conjugation is restricted to newly synthesized pools of proteins, and (3) Herc5 is physically associated with polyribosomes. These results lead to a model for ISGylation in which Herc5 broadly modifies newly synthesized proteins in a cotranslational manner. This further suggests that, in the context of an interferon-stimulated cell, newly translated viral proteins may be primary targets of ISG15. Consistent with this, we demonstrate that ISGylation of human papillomavirus (HPV) L1 capsid protein has a dominant-inhibitory effect on the infectivity of HPV16 pseudoviruses.
ISG15 是一种干扰素诱导的抗病毒泛素样蛋白 (Ubl)。Herc5 是 ISG15 的主要 E3 酶，可介导干扰素刺激细胞中超过 300 种蛋白质的 ISG 化。在研究 Herc5 的这种广泛的底物选择性时，我们发现：(1) 底物的范围甚至更广，包括许多外源表达的外来蛋白质；(2) ISG15 缀合仅限于新合成的蛋白质库；(3) Herc5 与多核糖体物理相关。这些结果提出了一种 ISG 化模型，其中 Herc5 以共翻译方式广泛修饰新合成的蛋白质。这进一步表明，在干扰素刺激的细胞中，新翻译的病毒蛋白可能是 ISG15 的主要靶标。与此一致，我们证明了 HPV L1 衣壳蛋白的 ISG 化对 HPV16 假病毒的感染性具有显性抑制作用。
