Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195.
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195
Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6798-6803. doi: 10.1073/pnas.1802114115. Epub 2018 Jun 11.
Detection of nucleic acids by innate immune sensors triggers the production of type I interferons (IFNs). While IFNs are essential for host defense against viral infection, dysregulated production of IFNs underlies numerous autoinflammatory diseases. We have found that the loss of sumoylation results in a potent, spontaneous IFN response. Vertebrates possess three small ubiquitin-like modifiers (SUMOs) that can be conjugated onto target proteins and alter protein function in diverse but still poorly characterized ways. We demonstrate that regulation of IFN by sumoylation is redundantly mediated by both SUMO2 and SUMO3, but not SUMO1, revealing a previously unknown function of SUMO2/3. Remarkably, this IFN response is independent of all known IFN-inducing pathways and does not require either of the canonical IFN-associated transcription factors IRF3 or IRF7. Taken together, our findings demonstrate that SUMO2 and SUMO3 are specific and essential negative regulators of a noncanonical mechanism of IFN induction.
先天免疫传感器检测到核酸会引发 I 型干扰素 (IFN) 的产生。虽然 IFN 对于宿主防御病毒感染至关重要，但 IFN 的失调产生是许多自身炎症性疾病的基础。我们发现，SUMO 化的缺失会导致强烈的、自发的 IFN 反应。脊椎动物拥有三种小泛素样修饰物 (SUMO)，可以连接到靶蛋白上，并以不同但仍知之甚少的方式改变蛋白质功能。我们证明，SUMO 化对 IFN 的调节是由 SUMO2 和 SUMO3 共同介导的，但不是 SUMO1，揭示了 SUMO2/3 的一个先前未知的功能。值得注意的是，这种 IFN 反应独立于所有已知的 IFN 诱导途径，也不需要经典的 IFN 相关转录因子 IRF3 或 IRF7。总之，我们的研究结果表明，SUMO2 和 SUMO3 是 IFN 诱导非经典机制的特异性和必需的负调节剂。
