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

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.

Impaired activation of Transposable Elements in SARS-CoV-2 infection

“…The outcome of the impaired TE upregulation is a reduced dysfunctional early IFN response, which may result in an exacerbated inflammatory response leading possibly to a cytokine storm, manifested clinically by severe acute respiratory distress syndrome (ARDS) with systemic consequences, such as disseminated intravascular coagulation (Garcia, 2020; Park and Iwasaki, 2020). This is in line with previous works which demonstrate the effectiveness of reverse transcriptase inhibitors as a treatment to reduce IFN activation (De Cecco et al, 2019; Tunbak et al, 2020). Therefore, we propose that TE activation could be used as a therapeutic tool to generate higher cellular IFN response against SARS-CoV-2 infection.…”

Endogenous retroviruses in the origins and treatment of cancer

“…In hematological datasets, expression from a diverse array of TEs, including ERVs, SINEs, and LINEs, has been linked with viral mimicry upon DNMTi treatment [ 182 ]. Inactivation of the HUSH complex component MPP8 leads to both ERV and L1 upregulation, with the latter associated with dsRNA production and a type I interferon response [ 183 ]. Global ERV expression levels have been found to not predict clinical response of myelodysplasias treated with DNMTis [ 184 ].…”

Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus

“…Epigenetic regulation is a fundamental mechanism employed by cells to silence genes whose actions are either not needed or are potentially deleterious [ 132 ]. This mechanism of transcriptional repression operates on L1 [ 132 ] and HERVs and is initiated by DNA methyltransferase 1 (DNMT1) [ 133 ], which methylates the 5-position of cytosine in genomic CpG islands, attracting several silencing factors such as the human silencing hub (HUSH) complex [ 134 ] and histone modifiers [ 135 ] to effectively suppress transcription. Next, RNA interference and silencing activities of small interfering RNAs (siRNAs), miRNAs, and Piwi-interacting RNAs (piRNAs) act to prevent retrotransposon mRNA translation [ 136 ].…”