The HUSH epigenetic repressor complex silences PML nuclear body-associated HSV-1 quiescent genomes
Herpes simplex virus 1 (HSV-1) latently infected neurons display diverse patterns in the distribution of the viral genomes within the nucleus. A key pattern involves quiescent HSV-1 genomes sequestered in promyelocytic leukemia nuclear bodies (PML NBs) forming viral DNA-containing PML-NBs (vDCP NBs). Using a cellular model that replicates vDCP NB formation, we previously demonstrated that these viral genomes are chromatinized with the H3.3 histone variant modified on its lysine 9 by trimethylation (H3.3K9me3), a mark associated with transcriptional repression. Here, we identify the HUSH complex and its effectors, SETDB1 and MORC2, as crucial for the acquisition of H3K9me3 on PML NB-associated HSV-1 and the maintenance of HSV-1 transcriptional repression. ChIP-seq analyses show H3K9me3 association with the entire viral genome. Inactivating the HUSH-SETDB1-MORC2 complex before infection significantly reduces H3K9me3 on the viral genome, with minimal impact on the cellular genome, aside from expected changes in LINE-1 retroelements. Depletion of HUSH, SETDB1, or MORC2 alleviates HSV-1 repression in infected primary human fibroblasts and human induced pluripotent stem cell-derived sensory neurons (hiPSDN). We found that the viral protein ICP0 induces MORC2 degradation via the proteasome machinery. This process is concurrent with ICP0 and MORC2 depletion capability to reactivate silenced HSV-1 in hiPSDN. Overall, our findings underscore the robust antiviral function of the HUSH-SETDB1-MORC2 repressor complex against a herpesvirus by modulating chromatin marks linked to repression, thus presenting promising avenues for anti-herpesvirus therapeutic strategies.
Authors
- Yonatan Ganor (ORCID: https://orcid.org/0000-0003-4430-7744)
- Oscar L. Haigh (ORCID: https://orcid.org/0000-0001-5022-4692)
- Franceline Juillard (ORCID: https://orcid.org/0000-0003-1449-3603)
- Tristan Escure (ORCID: https://orcid.org/0000-0002-0599-5727)
- Olivier Binda (ORCID: https://orcid.org/0000-0002-1539-0828)
- Simon Roubille
- Patrick Lomonte (ORCID: https://orcid.org/0000-0001-9248-648X)
- Marc Labétoulle (ORCID: https://orcid.org/0000-0002-1680-1887)
- Pascale Texier
- Stuart Bloor
- Armelle Corpet (ORCID: https://orcid.org/0000-0002-2126-5783)
- Olivier Pascual (ORCID: https://orcid.org/0000-0002-5730-9880)
- Camille Cohen (ORCID: https://orcid.org/0000-0002-5540-0306)
- Paul J. Lehner (ORCID: https://orcid.org/0000-0001-9383-1054)
- Mathilde Gonin (ORCID: https://orcid.org/0009-0004-3507-1148)
- Frédérique Magdinier
- Coline Seurre
- Rémi Néplaz (ORCID: https://orcid.org/0009-0004-3488-1720)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Ottawa (CA)
- Inserm (FR)
- Institut Universitaire de France (FR)
- Université de Montpellier (FR)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Centre hospitalier national d'ophtalmologie des Quinze-Vingts (FR)
- CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Institut NeuroMyoGène (FR)
- CEA Paris-Saclay (FR)
- Institut Cochin (FR)
- Institut Supérieur des Biotechnologies de Paris (FR)
- MRC Epidemiology Unit (GB)
- Bicêtre Hospital (FR)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1073/pnas.2412258121
- Citations
- 11
- Primary Topic
- Herpesvirus Infections and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.25
Funders
- Wellcome Trust
- University of Glasgow
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Université Paris Diderot
- Medical Research Council
- Center for Virus Research, University of California, Irvine
- CHIST-ERA