Competition between two HUSH complexes orchestrates the immune response to retroelement invasion
- Mol Cell. 2024 Aug 8;84(15):2870-2881.e5. doi: 10.1016/j.molcel.2024.06.020.
- 1. The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
- 2. Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
- 3. Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge CB2 0AW, UK.
- 4. The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK. Electronic address: [email protected].
The human silencing hub (HUSH) preserves genome integrity through the epigenetic repression of invasive genetic elements. However, despite our understanding of HUSH as an obligate complex of three subunits, only loss of MPP8 or Periphilin, but not TASOR, triggers interferon signaling following derepression of endogenous retroelements. Here, we resolve this paradox by characterizing a second HUSH complex that shares MPP8 and Periphilin but assembles around TASOR2, an uncharacterized paralog of TASOR. Whereas HUSH represses LINE-1 retroelements marked by the repressive histone modification H3K9me3, HUSH2 is recruited by the transcription factor IRF2 to repress interferon-stimulated genes. Mechanistically, HUSH-mediated retroelement silencing sequesters the limited pool of the shared subunits MPP8 and Periphilin, preventing TASOR2 from forming HUSH2 complexes and hence relieving the HUSH2-mediated repression of interferon-stimulated genes. Thus, competition between two HUSH complexes intertwines retroelement silencing with the induction of an immune response, coupling epigenetic and immune aspects of genome defense.