Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London, E1 2AT, UK.
Infection and Immunity, University College London, London, WC1E 6BT, UK.
Nat Commun. 2020 Nov 3;11(1):5387. doi: 10.1038/s41467-020-19170-5.
The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs (dsRNAs). This coincides with upregulation of primate-conserved LINE-1s, as well as increased expression of full-length hominid-specific LINE-1s that produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs can abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct activates interferon signaling. Finally, we show that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through dsRNA sensing and gene-regulatory roles and are controlled by the HUSH complex.
人类沉默中心（HUSH）复合物对于 LINE-1 元件的表观遗传抑制是必要的。我们表明，在人类细胞系和原代成纤维细胞中 HUSH 的耗竭会通过 JAK/STAT 信号导致干扰素刺激基因（ISGs）的诱导。这种效应主要归因于 MDA5 和 RIG-I 对双链 RNA（dsRNA）的感应。这与灵长类动物保守的 LINE-1 的上调以及全长同源人特异性 LINE-1 的表达增加相一致，后者产生双向 RNA，可能形成 dsRNA。值得注意的是，ISG 附近的 LTRs 可能被去抑制，从而使这些基因对干扰素更敏感。LINE-1 shRNAs 可以消除 HUSH 依赖性反应，而工程 LINE-1 构建体的过表达会激活干扰素信号。最后，我们表明，HUSH 成分 MPP8 在多种癌症中经常下调，其耗竭会导致 DNA 损伤。这些结果表明，LINE-1s 可能通过 dsRNA 感应和基因调控作用驱动生理或自身炎症反应，并受 HUSH 复合物的控制。
