The HUSH epigenetic repressor complex silences PML nuclear body-associated HSV-1 quiescent genomes.

Autor:	Roubille S; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France., Escure T; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France., Juillard F; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France.; SupBiotech Research Department - CellTechs Laboratory, SupBiotech, Lyon 69003, France., Corpet A; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France.; Institut Universitaire de France (IUF), Paris 75005, France., Néplaz R; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France., Binda O; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France.; Faculty of Medicine Department of Cellular and Molecular Medicine University of Ottawa, Ottawa, ON K1H 8M5, Canada., Seurre C; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France., Gonin M; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France., Bloor S; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge CB2 OAW, United Kingdom., Cohen C; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France.; Université Montpellier, Centre national de la recherche scientifique (CNRS) UMR5294, Laboratory of Pathogen Host Interactions (LPHI), team 'GATAC-Malaria', Montpellier 34095, France., Texier P; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France., Haigh O; Université Paris-Saclay, Institut national de la santé et de la recherche médicale (Inserm), U1184, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB). Commissariat à l'Énergie Atomique et aux Énergies renouvelables (CEA), Fontenay-aux-Roses 92260, France., Pascual O; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5284, Institut national de la santé et de la recherche médicale (Inserm) U1314, Institut NeuroMyoGène-Mechanisms in Integrated Life Sciences (INMG-MeLiS), Team 'Synaptopathies et Autoanticorps', Lyon 69008, France., Ganor Y; Université Paris Cité, Institut Cochin, Centre national de la recherche scientifique (CNRS) UMR 8104, Institut national de la santé et de la recherche médicale (Inserm) U1016, Paris 75014, France., Magdinier F; Université Aix-Marseille, Institut national de la santé et de la recherche médicale (Inserm) U1251, Marseille Medical Genetics (MMG), team 'Epigenetic and nucleoskeleton dynamics in rare diseases', Marseille 13385, France., Labetoulle M; Université Paris-Saclay, Institut national de la santé et de la recherche médicale (Inserm), U1184, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB). Commissariat à l'Énergie Atomique et aux Énergies renouvelables (CEA), Fontenay-aux-Roses 92260, France.; Université Paris-Saclay, Service d'Ophtalmologie, Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris (AP-HP), Centre de Recherche Maladies Rares (CMR), Centre de référence des maladies rares en ophtalmologie (OPHTARA), Le Kremlin-Bicêtre 94270, France.; Service d'Ophtalmologie, Hôpital National de la Vision des Quinze-Vingts, Institut Hospitalo-universitaire (IHU) FOReSIGHT, Paris 75012, France., Lehner PJ; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge CB2 OAW, United Kingdom., Lomonte P; Université Claude Bernard Lyon 1, Centre national de la recherche scientifique (CNRS) UMR 5261, Institut national de la santé et de la recherche médicale (Inserm) U1315, Laboratoire d'Excellence (LabEx) DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle (INMG-PGNM), team 'Chromatin dynamics, Nuclear Domains, Virus', Lyon 69008, France.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Dec 03; Vol. 121 (49), pp. e2412258121. Date of Electronic Publication: 2024 Nov 26.
DOI:	10.1073/pnas.2412258121
Abstrakt:	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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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