The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s


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Authors
Tunbak, Hale 
Enriquez-Gasca, Rocio  ORCID logo  https://orcid.org/0000-0002-0483-4841
Tie, Christopher H. C. 
Gould, Poppy A. 
Mlcochova, Petra 
Abstract

Abstract: 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.

Description

Funder: UKRI Future Leaders Fellowship (MR/S034498/1)

Keywords
Article, /631/67/68/2486, /631/208/176/2016, /631/250/262/2106/2518, /631/337/1427/2566, /38, /38/44, /38/89, /38/91, /38/88, /38/1, article
Journal Title
Nature Communications
Conference Name
Journal ISSN
2041-1723
Volume Title
11
Publisher
Nature Publishing Group UK
Sponsorship
Wellcome Trust (Wellcome) (101200/Z/13/Z, WT108082AIA, WT108082AIA, 101200/Z/13/Z, 101200/Z/13/Z)
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) (678350, 678350, 678350, 678350)
Rosetrees Trust (A2630)