Pathogens use virulence factors to inhibit the immune system¹. The guard hypothesis^2,3 postulates that hosts monitor (or ‘guard’) critical innate immune pathways such that their disruption by virulence factors provokes a secondary immune response¹. Here we describe a ‘self-guarded’ immune pathway in human monocytes, in which guarding and guarded functions are combined in one protein. We find that this pathway is triggered by ICP0, a key virulence factor of herpes simplex virus type 1, resulting in robust induction of anti-viral type I interferon (IFN). Notably, induction of IFN by ICP0 is independent of canonical immune pathways and the IRF3 and IRF7 transcription factors. A CRISPR screen identified the ICP0 target MORC3⁴ as an essential negative regulator of IFN. Loss of MORC3 recapitulates the IRF3- and IRF7-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. As well as repressing the MRE to regulate IFNB1, MORC3 is also a direct restriction factor of HSV-1⁵. 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.

病原体利用毒力因子来抑制免疫系统¹ 。守卫假说^2,3假设宿主监控（或“守卫”）关键的先天免疫途径，以便它们被毒力因子破坏从而引发二次免疫反应¹ 。在这里，我们描述了人类单核细胞中的一种“自我保护”免疫途径，其中保护和被保护功能结合在一种蛋白质中。我们发现该途径是由 ICP0（1 型单纯疱疹病毒的关键毒力因子）触发的，从而强烈诱导抗病毒 I 型干扰素 (IFN)。值得注意的是，ICP0 诱导 IFN 独立于经典免疫途径以及 IRF3 和 IRF7 转录因子。 CRISPR 筛选鉴定出 ICP0 靶标 MORC3 ⁴是 IFN 的重要负调节因子。 MORC3的缺失重现了 ICP0 诱导的 IRF3 和 IRF7 独立的 IFN 反应。从机制上讲，ICP0 会降解 MORC3，从而导致与IFNB1位点相邻的 MORC3 调节的 DNA 元件 (MRE) 去抑制。 MORC3 途径诱导IFNB1需要顺式MRE，但经典 IFN 诱导途径不需要 MRE。除了抑制MRE 来调节IFNB1外，MORC3 也是HSV-1 ⁵的直接限制因子。因此，我们的结果提出了一个模型，其中 MORC3 的主要抗病毒功能由其次要 IFN 抑制功能自我保护，因此，降解 MORC3 以避免其主要抗病毒功能的病毒将释放次要抗病毒功能。干扰素反应。