Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
J Immunol. 2013 Mar 1;190(5):2311-9. doi: 10.4049/jimmunol.1202749. Epub 2013 Jan 23.
The innate immune system is important for control of infections, including herpesvirus infections. Intracellular DNA potently stimulates antiviral IFN responses. It is known that plasmacytoid dendritic cells sense herpesvirus DNA in endosomes via TLR9 and that nonimmune tissue cells can sense herpesvirus DNA in the nucleus. However, it remains unknown how and where myeloid cells, such as macrophages and conventional dendritic cells, detect infections with herpesviruses. In this study, we demonstrate that the HSV-1 capsid was ubiquitinated in the cytosol and degraded by the proteasome, hence releasing genomic DNA into the cytoplasm for detection by DNA sensors. In this context, the DNA sensor IFN-γ-inducible 16 is important for induction of IFN-β in human macrophages postinfection with HSV-1 and CMV. Viral DNA localized to the same cytoplasmic regions as did IFN-γ-inducible 16, with DNA sensing being independent of viral nuclear entry. Thus, proteasomal degradation of herpesvirus capsids releases DNA to the cytoplasm for recognition by DNA sensors.
先天免疫系统对于控制感染（包括疱疹病毒感染）非常重要。细胞内 DNA 能够强烈刺激抗病毒 IFN 反应。已知浆细胞样树突状细胞通过 TLR9 在内涵体内感知疱疹病毒 DNA，而非免疫组织细胞可以在细胞核内感知疱疹病毒 DNA。然而，髓系细胞（如巨噬细胞和常规树突状细胞）如何以及在何处检测疱疹病毒感染仍不清楚。在这项研究中，我们证明了 HSV-1 衣壳在细胞质中被泛素化，并被蛋白酶体降解，从而将基因组 DNA 释放到细胞质中，以供 DNA 传感器检测。在这种情况下，IFN-γ诱导的 16 是人类巨噬细胞感染 HSV-1 和 CMV 后诱导 IFN-β 的重要因素。病毒 DNA 与 IFN-γ诱导的 16 定位在相同的细胞质区域，DNA 感应不依赖于病毒核进入。因此，疱疹病毒衣壳的蛋白酶体降解将 DNA释放到细胞质中，以供 DNA 传感器识别。
