In cell-intrinsic antiviral immunity, cytoplasmic receptors such as retinoic acid-inducible gene I (RIG-I) detect viral double-stranded RNA (dsRNA) and trigger a signaling cascade activating the interferon (IFN) system. This leads to the transcription of hundreds of interferon-stimulated genes (ISGs) with a wide range of antiviral effects. This recognition of dsRNA not only has to be very specific to discriminate foreign from self but also highly sensitive to detect even very low numbers of pathogenic dsRNA molecules. Previous work indicated an influence of the dsRNA length on the binding behavior of RIG-I and its potential to elicit antiviral signaling. However, the molecular mechanisms behind the binding process are still under debate. We compare two hypothesized RIG-I binding mechanisms by translating them into mathematical models and analyzing their potential to describe published experimental data. The models consider the length of the dsRNA as well as known RIG-I binding motifs and describe RIG-I pathway activation after stimulation with dsRNA. We show that internal RIG-I binding sites in addition to cooperative RIG-I oligomerization are essential to describe the experimentally observed RIG-I binding behavior and immune response activation for different dsRNA lengths and concentrations. The combination of RIG-I binding to internal sites on the dsRNA and cooperative oligomerization compensates for a lack of high-affinity binding motifs and triggers a strong antiviral response for long dsRNAs. Model analysis reveals dsRNA length-dependency as a potential mechanism to discriminate between different types of dsRNAs: It allows for sensitive detection of small numbers of long dsRNAs, a typical by-product of viral replication, while ensuring tolerance against non-harming small dsRNAs.

中文翻译：

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机制建模解释了RIG-I介导的免疫反应的dsRNA长度依赖性激活。

在细胞内在的抗病毒免疫中，诸如视黄酸诱导基因I（RIG-I）的胞质受体检测病毒双链RNA（dsRNA）并触发信号传导级联，从而激活干扰素（IFN）系统。这导致数百种具有广泛抗病毒作用的干扰素刺激基因（ISG）转录。对dsRNA的这种识别不仅必须具有非常高的特异性，以区分异物与自身，而且对检测甚至极少量的致病性dsRNA分子也非常敏感。先前的工作表明了dsRNA长度对RIG-1的结合行为的影响及其引发抗病毒信号的潜力。然而，结合过程背后的分子机制仍在争论中。我们通过将两种假设的RIG-I结合机制转化为数学模型并分析其描述已发布实验数据的潜力，来比较它们。该模型考虑了dsRNA的长度以及已知的RIG-I结合基序，并描述了用dsRNA刺激后RIG-I途径的激活。我们显示，内部RIG-I结合位点以及协作RIG-I寡聚化对于描述实验观察到的RIG-I结合行为和不同dsRNA长度和浓度的免疫应答激活至关重要。RIG-1与dsRNA的内部位点结合以及协同寡聚的结合可弥补缺乏高亲和力的结合基序，并引发长dsRNA的强烈抗病毒反应。