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

  • Nat Commun. 2020 Nov 3;11(1):5387. doi: 10.1038/s41467-020-19170-5.
Hale Tunbak  #  1 ,  Rocio Enriquez-Gasca  #  1 ,  Christopher H C Tie  2 ,  Poppy A Gould  1 ,  Petra Mlcochova  3 ,  Ravindra K Gupta  3 ,  Liane Fernandes  1 ,  James Holt  1 ,  Annemarthe G van der Veen  4  5 ,  Evangelos Giampazolias  4 ,  Kathleen H Burns  6 ,  Pierre V Maillard  1 ,  Helen M Rowe  7
Affiliations
  • 1. Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London, E1 2AT, UK.
  • 2. Infection and Immunity, University College London, London, WC1E 6BT, UK.
  • 3. Department of Medicine, University of Cambridge, CB2 0AF, Cambridge, UK.
  • 4. The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 5. Leiden University Medical Centre, Department of Immunohematology and Blood Transfusion, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
  • 6. Department of Pathology, John Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
  • 7. Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London, E1 2AT, UK. [email protected].
  • # Contributed equally.
PMID: 33144593 DOI: 10.1038/s41467-020-19170-5
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.