Splitting STAT Dimers to Understand Interferon Balance: A Strategy to Dissociate Beneficial and Detrimental Interferon Effects in Infection?

干扰素(IFN)是一种天然存在的信号蛋白，近60年前因其强大的抗病毒特性而被发现。现在人们普遍认识到，干扰素是抵御有害微生物的重要第一道防线，而且是控制正常细胞和肿瘤细胞生存的关键免疫调节剂。因此，IFN被用于治疗各种严重疾病，包括癌症、多发性硬化症和病毒性肝炎，目前的临床试验评估IFN是否也能预防SARS感染的严重疾病。IFN的作用机制错综复杂，涉及到几个转录复合体，它们在两条不同的信号通路中发挥作用，目前仍不清楚。在动态过程的研究中有特别的障碍，例如涉及瞬时蛋白质相互作用的干扰素信号，以及大型蛋白质复合体从细胞膜到细胞核的快速移位。蛋白质生产的进步和我们实验室开发的可视化关键信号事件的新分析方法为研究这些多方面的过程打开了新的途径，我们现在有了必要的工具来详细研究干扰素信号的分子基础。通过分子解剖STAT转录因子复合体，我们可以首次揭示平衡I型和II型干扰素途径的关键决定因素。我们的初步结果提出了这样一个前景，即STAT二聚体的分裂构成了以受控方式重新平衡干扰素反应的新策略。这反过来又对一些重要的微生物感染特别感兴趣，在这些感染中，I型和II型拮抗型干扰素反应破坏了宿主保护。这项拟议的研究将导致对我们免疫系统核心方面的基础知识的一步改变，从而也大大推进了对干扰素调节的精确药物的未得到满足的探索。

Interferons (IFNs) are naturally occurring signalling proteins that were discovered almost 60 years ago due to their potent anti-viral properties. It is now generally appreciated that interferons constitute the vital first line of defence against harmful microbes, and moreover function as key immune modulators that control the survival of normal and tumour cells. Accordingly, IFNs are used for treating various serious conditions including cancers, multiple sclerosis and viral hepatitis, and current clinical trials assess if IFNs also protect from serious illness in SARS infections. The mechanism of action of IFNs is intricate, involves several transcription complexes that function in two distinct signalling pathways, and is still not well understood. There are particular hurdles in the study of dynamic processes such as IFN signalling that involve transient protein interactions and the rapid translocation of large protein complexes from the cell membrane to the nucleus. Advances in protein production and new assays developed in our lab that visualize crucial signalling events have opened the door to new ways to study these multifaceted processes, and we now have the necessary tools we need to examine the molecular underpinnings of IFN signalling in detail. By molecularly dissecting STAT transcription factor complexes we can for the first time lay bare key determinants for balancing the type I and type II IFN pathways. Our preliminary results raise the prospect that the splitting of STAT dimers constitutes a novel strategy for rebalancing IFN responses in a controlled manner. This, in turn, is of particular interest regarding a number of important microbial infections, where antagonistic type I and type II IFN responses damage host protection. The proposed research will lead to a step change in the fundamental knowledge of a central aspect of our immune system, and thus also considerably advance the unmet quest for interferon-modulating precision medicines.