Langevin Christelle, Aleksejeva Elina, Houel Armel, Briolat Valérie, Torhy Corinne, Lunazzi Aurélie, Levraud Jean-Pierre, Boudinot Pierre
INRA, Virologie et Immunologie Moléculaires, Jouy-en-Josas, France.
Institut Pasteur, Unité Macrophages et Développement de l'Immunité, Paris, France.
Front Immunol. 2017 May 26;8:617. doi: 10.3389/fimmu.2017.00617. eCollection 2017.
Tripartite motif (TRIM) proteins are involved in various cellular functions and constitute key factors of the antiviral innate immune response. TRIM proteins can bind viral particles directly, sending them to degradation by the proteasome, or ubiquitinate signaling molecules leading to upregulation of innate immunity. TRIM proteins are present in across metazoans but are particularly numerous in vertebrates where genes comprising a B30.2 domain have been often duplicated. In fish, a TRIM subset named finTRIM is highly diversified, with large gene numbers and clear signatures of positive selection in the B30.2 domain suggesting they may be involved in antiviral mechanisms. finTRIM provides a beautiful model to investigate the primordial implication of B30.2 TRIM subsets in the arsenal of vertebrate antiviral defenses. We show here that , a zebrafish gene mainly expressed in the gills, skin and pharynx, encodes a protein affording a potent antiviral activity. , overexpression of FTR83, but not of its close relative FTR82, induced IFN and IFN-stimulated gene expression and afforded protection against different enveloped and non-enveloped RNA viruses. The kinetics of IFN induction paralleled the development of the antiviral activity, which was abolished by a dominant negative IRF3 mutant. In the context of a viral infection, FTR83 potentiated the IFN response. Expression of chimeric proteins in which the B30.2 domain of FTR83 and the non-protective FTR82 had been exchanged, showed that IFN upregulation and antiviral activity requires both the Ring/BBox/Coiled coil domain (supporting E3 ubiquitin ligase) and the B30.2 domain of FTR83. Finally, loss of function experiments in zebrafish embryos confirms that ftr83 mediates antiviral activity . Our results show that a member of the largest TRIM subset observed in fish upregulates type I IFN response and afford protection against viral infections, supporting that TRIMs are key antiviral factors across vertebrates.
三聚体基序（TRIM）蛋白参与多种细胞功能，是抗病毒天然免疫反应的关键因子。TRIM蛋白可直接结合病毒颗粒，将其送至蛋白酶体降解，或使信号分子泛素化，从而导致天然免疫上调。TRIM蛋白存在于所有后生动物中，但在脊椎动物中数量尤其众多，其中包含B30.2结构域的基因常常发生复制。在鱼类中，一个名为鳍TRIM（finTRIM）的TRIM亚群高度多样化，基因数量众多，且在B30.2结构域中有明显的正选择特征，表明它们可能参与抗病毒机制。鳍TRIM为研究B30.2 TRIM亚群在脊椎动物抗病毒防御武器库中的原始作用提供了一个很好的模型。我们在此表明，斑马鱼的一个主要在鳃、皮肤和咽部表达的基因，编码一种具有强大抗病毒活性的蛋白质。FTR83的过表达，而非其近亲FTR82的过表达，可诱导干扰素（IFN）和IFN刺激基因的表达，并提供针对不同包膜和非包膜RNA病毒的保护。IFN诱导的动力学与抗病毒活性的发展平行，而一种显性负性IRF3突变体可消除这种活性。在病毒感染的情况下，FTR83增强了IFN反应。表达嵌合蛋白（其中FTR83的B30.2结构域与无保护作用的FTR82结构域进行了交换）表明，IFN上调和抗病毒活性需要FTR83的环/盒状结构域/卷曲螺旋结构域（支持E3泛素连接酶）和B30.2结构域。最后，斑马鱼胚胎中的功能丧失实验证实ftr83介导抗病毒活性。我们的结果表明，在鱼类中观察到的最大TRIM亚群的一个成员上调了I型IFN反应，并提供针对病毒感染的保护，支持TRIM是整个脊椎动物中的关键抗病毒因子。
