Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC, Australia.
Department of Chemistry and Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
Immunol Cell Biol. 2021 Apr;99(4):373-391. doi: 10.1111/imcb.12420. Epub 2020 Nov 22.
Viperin is an interferon-inducible protein that is pivotal for eliciting an effective immune response against an array of diverse viral pathogens. Here we describe a mechanism of viperin's broad antiviral activity by demonstrating the protein's ability to synergistically enhance the innate immune dsDNA signaling pathway to limit viral infection. Viperin co-localized with the key signaling molecules of the innate immune dsDNA sensing pathway, STING and TBK1; binding directly to STING and inducing enhanced K63-linked polyubiquitination of TBK1. Subsequent analysis identified viperin's necessity to bind the cytosolic iron-sulfur assembly component 2A, to prolong its enhancement of the type-I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signaling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signaling pathway, which results in an enhanced antiviral state. We also provide evidence for viperin's radical SAM enzymatic activity to self-limit its immunomodulatory functions. These data further define viperin's role as a positive regulator of innate immune signaling, offering a mechanism of viperin's broad antiviral capacity.
Viperin 是一种干扰素诱导蛋白，对引发针对多种不同病毒病原体的有效免疫反应至关重要。在这里，我们通过证明该蛋白能够协同增强先天免疫 dsDNA 信号通路来限制病毒感染，从而描述了 Viperin 广泛抗病毒活性的机制。Viperin 与先天免疫 dsDNA 传感途径的关键信号分子 STING 和 TBK1 共定位; 直接与 STING 结合，并诱导 TBK1 的增强的 K63 连接多聚泛素化。随后的分析确定了 Viperin 结合细胞质铁硫组装成分 2A 的必要性，以延长其对异常 dsDNA 的 I 型干扰素反应的增强作用。在这里，我们表明 Viperin 有助于形成信号增强子，以协调 dsDNA 信号通路激活后的有效信号转导，从而导致增强的抗病毒状态。我们还提供了 Viperin 的自由基 SAM 酶活性自我限制其免疫调节功能的证据。这些数据进一步定义了 Viperin 作为先天免疫信号的正调节剂的作用，提供了 Viperin 广泛抗病毒能力的机制。
