Self-guarding of MORC3 enables virulence factor-triggered immunity.
Self-guarding of MORC3 enables virulence factor-triggered immunity.
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DOI：
10.1038/s41586-021-04054-5
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发表时间：
2021-12
期刊：
影响因子：
64.8
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中科院分区：
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病原体利用毒力因子来抑制免疫系统。守卫假说假设宿主监控（或“守卫”）关键的先天免疫途径，使其被毒力因子破坏，引发二次免疫应答。在这里，我们描述了一个“自我保护”的免疫途径在人类单核细胞，其中保护和被保护的功能是统一的一个蛋白质。我们发现，这一途径是由ICP 0，一个关键的毒力因子单纯疱疹病毒-1（HSV-1），导致在强大的诱导抗病毒I型干扰素（IFN）。令人惊讶的是，由ICP 0诱导的IFN不依赖于典型的免疫途径和IRF 3/7转录因子。CRISPR筛选将ICP 0靶向MORC 3鉴定为IFN的重要负调节因子。M0 RC 3的缺失再现了ICP 0诱导的IRF 3/7非依赖性IFN应答。在机制上，ICP 0降解MORC 3，这导致与IFNB 1基因座相邻的MORC 3调节的DNA元件（MRE）的去阻遏。MRE对于通过MORC 3途径的IFNB 1诱导是顺式需要的，但对于典型的IFN诱导途径不是必需的。MORC 3除了通过抑制MRE来调节IFNB 1外，还是HSV-1的直接限制因子。因此，我们的研究结果提出了一种模型，其中MORC 3的主要抗病毒功能是由其次要IFN抑制功能“自我保护”：因此，降解MORC 3以避免其主要抗病毒功能的病毒将释放次要抗病毒IFN应答。
Pathogens employ virulence factors to inhibit the immune system. The guard hypothesis postulates that hosts monitor (or ‘guard’) critical innate immune pathways such that their disruption by virulence factors provokes a secondary immune response. Here, we describe a ‘self-guarded’ immune pathway in human monocytes, in which guarding and guarded functions are united in one protein. We find that this pathway is triggered by ICP0, a key virulence factor of Herpes Simplex Virus-1 (HSV-1), resulting in robust induction of anti-viral type I interferon (IFN). Surprisingly, induction of IFN by ICP0 is independent of canonical immune pathways and the IRF3/7 transcription factors. A CRISPR-screen identified the ICP0-target MORC3 as an essential negative regulator of IFN. Loss of MORC3 recapitulates the IRF3/7-independent IFN response induced by ICP0. Mechanistically, ICP0 degrades MORC3, which leads to de-repression of a MORC3-regulated DNA element (MRE) adjacent to the IFNB1 locus. The MRE is required in cis for IFNB1 induction by the MORC3 pathway, but is not required for canonical IFN-inducing pathways. Besides repressing the MRE to regulate IFNB1, MORC3 is also a direct restriction factor of HSV-1. Our results thus suggest a model in which the primary anti-viral function of MORC3 is ‘self-guarded’ by its secondary IFN-repressing function: thus, a virus that degrades MORC3 to avoid its primary anti-viral function will unleash the secondary anti-viral IFN response.
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