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

• 成果类型: Article
• 署名作者: Roubille, Simon; Escure, Tristan; Juillard, Franceline; Corpet, Armelle; Neplaz, Remi; Binda, Olivier; Seurre, Coline; Gonin, Mathilde; Bloor, Stuart; Cohen, Camille; Texier, Pascale; Haigh, Oscar; Pascual, Olivier; Ganor, Yonatan; Magdinier, Frederique; Labetoulle, Marc; Lehner, Paul J.; Lomonte, Patrick
• 署名单位: Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Claude Bernard Lyon 1; Institut Universitaire de France; University of Ottawa; Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); CEA; Universite Paris Saclay; Universite Claude Bernard Lyon 1; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Aix-Marseille Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Bicetre - APHP; Hopital Universitaire Antoine-Beclere - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Saclay
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12286
• DOI: 10.1073/pnas.2412258121
• 发表日期: 2024-12-03
• 关键词: simplex-virus type-1; marie-tooth disease; methyltransferase; protein; reactivation; bodies; cells; heterochromatin; RESTRICTION; inhibition

摘要

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 antiherpesvirus therapeutic strategies.