Department of Infectious Diseases, University of Georgia, Athens, GA, United States.
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, United States.
Front Immunol. 2022 Jan 4;12:794664. doi: 10.3389/fimmu.2021.794664. eCollection 2021.
Post-translational modification of host and viral proteins by ubiquitin and ubiquitin-like proteins plays a key role in a host's ability to mount an effective immune response. Avian species lack a ubiquitin-like protein found in mammals and other non-avian reptiles; interferon stimulated gene product 15 (ISG15). ISG15 serves as a messenger molecule and can be conjugated to both host and viral proteins leading them to be stabilized, degraded, or sequestered. Structurally, ISG15 is comprised of a tandem ubiquitin-like domain (Ubl), which serves as the motif for post-translational modification. The 2'-5' oligoadenylate synthetase-like proteins (OASL) also encode two Ubl domains in series near its C-terminus which binds OASL to retinoic acid inducible gene-I (RIG-I). This protein-protein interaction increases the sensitivity of RIG-I and results in an enhanced production of type 1 interferons and a robust immune response. Unlike human and other mammalian OASL homologues, avian OASLs terminate their tandem Ubl domains with the same LRLRGG motif found in ubiquitin and ISG15, a motif required for their conjugation to proteins. Chickens, however, lack RIG-I, raising the question of structural and functional characteristics of chicken OASL (chOASL). By investigating chOASL, the evolutionary history of viruses with deubiquitinases can be explored and drivers of species specificity for these viruses may be uncovered. Here we show that the chOASL tandem Ubl domains shares structural characteristics with mammalian ISG15, and that chOASL can oligomerize and conjugate to itself. In addition, the ISG15-like features of avian OASLs and how they impact interactions with viral deubiquitinases and deISGylases are explored.
泛素和类泛素蛋白对宿主和病毒蛋白的翻译后修饰在宿主产生有效免疫反应的能力中起着关键作用。禽类缺乏在哺乳动物和其他非禽类爬行动物中发现的一种类泛素蛋白；干扰素刺激基因产物 15（ISG15）。ISG15 作为一种信使分子，可以与宿主和病毒蛋白结合，使它们稳定、降解或隔离。在结构上，ISG15 由串联泛素样结构域（Ubl）组成，该结构域是翻译后修饰的基序。2'-5'寡聚腺苷酸合成酶样蛋白（OASL）也在其 C 末端附近串联编码两个 Ubl 结构域，将 OASL 与维甲酸诱导基因-I（RIG-I）结合。这种蛋白质-蛋白质相互作用增加了 RIG-I 的敏感性，导致 1 型干扰素的产生增加和强烈的免疫反应。与人类和其他哺乳动物 OASL 同源物不同，禽类 OASL 在其串联 Ubl 结构域的末端带有与泛素和 ISG15 相同的 LRLRGG 基序，该基序是将它们与蛋白质结合所必需的。然而，鸡缺乏 RIG-I，这就提出了鸡 OASL（chOASL）的结构和功能特征的问题。通过研究 chOASL，可以探索具有去泛素化酶的病毒的进化历史，并揭示这些病毒的物种特异性的驱动因素。在这里，我们表明 chOASL 的串联 Ubl 结构域与哺乳动物的 ISG15 具有相似的结构特征，并且 chOASL 可以寡聚化并与自身结合。此外，还探讨了禽类 OASL 的 ISG15 样特征以及它们如何影响与病毒去泛素化酶和去 ISGylases 的相互作用。
