小柯机器人

美国加州大学Russell E. Vance、Moritz M. Gaidt研究团队发现MORC3的自保护功能可诱导靶向毒力因子的免疫反应。相关论文于2021年11月10日发表于国际学术期刊《自然》杂志。

在本研究中，研究人员揭示了人单核细胞中的“自我保护”免疫途径，其中预防和保护功能由同一个蛋白介导。研究发现该途径由ICP0触发，ICP0是1型单纯疱疹病毒的关键毒力因子，强烈诱导抗病毒I型干扰素(IFN)的产生。值得注意的是，ICP0对IFN的诱导不依赖于经典免疫途径以及转录因子IRF3和IRF7。CRISPR筛选发现ICP0的靶点MORC3是IFN的基本负调节因子。MORC3缺失重现了由ICP0诱导的不依赖于IRF3和IRF7的IFN反应。

从机制上讲，ICP0通过降解MORC3导致与IFNB1基因座相邻MORC3调控DNA元件(MRE)的去抑制。MRE是MORC3途径诱导IFNB1顺式需要的，而非经典IFN诱导途径所必需。除了抑制MRE以调节IFNB1外，MORC3还是HSV-15的直接限制因子。因此，该研究结果提出了一个模型，即MORC3的主要抗病毒功能通过次级抑制IFN从而得到自我保护-因此，病毒通过降解MORC3来避免主要抗病毒反应的行为将激活免疫系统产生次级抗病毒干扰素反应。

据介绍，病原体使用毒力因子来抑制免疫反应。保守假说认为宿主监控（或“守卫”）是关键的先天免疫通路，它们被毒力因子破坏会引发二次免疫反应。

附：英文原文

Title: Self-guarding of MORC3 enables virulence factor-triggered immunity

Author: Gaidt, Moritz M., Morrow, Alyssa, Fairgrieve, Marian R., Karr, Jonathan P., Yosef, Nir, Vance, Russell E.

Issue&Volume: 2021-11-10

Abstract: Pathogens use virulence factors to inhibit the immune system1. The guard hypothesis2,3 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.

DOI: 10.1038/s41586-021-04054-5

Source: https://www.nature.com/articles/s41586-021-04054-5

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