SUMO2 and SUMO3 redundantly prevent a noncanonical type I interferon response.
SUMO2 and SUMO3 redundantly prevent a noncanonical type I interferon response.
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DOI：
10.1073/pnas.1802114115
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发表时间：
2018-06-26
影响因子：
11.1
通讯作者：
Stetson DB
中科院分区：
文献类型：
--
作者：
Crowl JT;Stetson DB
I型干扰素(IFN)是宿主抵御病毒感染所必需的细胞因子，但当它们产生不当时，会导致人类严重的自身免疫性疾病。我们发现，蛋白质修饰的苏莫化途径对于防止异位干扰素反应是必不可少的。具体地说，我们已经确定SUMO2和SUMO3是两个冗余地阻止干扰素产生的相扑蛋白。值得注意的是，由SUMO2/3缺失引起的有效的干扰素反应不依赖于所有已知的抗病毒反应的诱导剂，揭示了一种独特的干扰素产生机制，这对我们理解抗病毒免疫具有重要意义。先天免疫传感器对核酸的检测会触发I型干扰素(IFN)的产生。虽然IFN对于宿主抵御病毒感染是必不可少的，但IFN的异常产生是许多自体炎症性疾病的基础。我们已经发现，缺失相思甲基化导致了一种有效的自发干扰素反应。脊椎动物拥有三个小的泛素样修饰物(SUMO)，它们可以结合到靶蛋白上，以不同的方式改变蛋白质的功能，但仍然缺乏特征性。我们证明了SUMO2和SUMO3对干扰素的调节是由SUMO2和SUMO3冗余地介导的，而不是由SUMO1介导的，这揭示了SUMO2/3的一个先前未知的功能。值得注意的是，这种干扰素反应独立于所有已知的干扰素诱导途径，并且不需要典型的干扰素相关转录因子IRF3或IRF7。综上所述，我们的研究结果表明，SUMO2和SUMO3是干扰素诱导的非规范机制的特异性和必要的负调控因子。
Type I interferons (IFNs) are cytokines that are essential for host defense against virus infection, but when they are inappropriately produced, they can cause severe autoimmune disease in humans. We have found that the sumoylation pathway of protein modification is essential for preventing an ectopic IFN response. Specifically, we have identified SUMO2 and SUMO3 as the two SUMO proteins that redundantly prevent IFN production. Remarkably, the potent IFN response caused by loss of SUMO2/3 is independent of all known inducers of the antiviral response, revealing a distinct mechanism of IFN production that has implications for our understanding of antiviral immunity. 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.
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