KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control

Tie, C. H.C. et al. (2018) KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control. EMBO Reports, 19(10), e45000. (doi: 10.15252/embr.201745000) (PMID:30061100) (PMCID:PMC6172469)

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Endogenous retroviruses (ERVs) have accumulated in vertebrate genomes and contribute to the complexity of gene regulation. KAP1 represses ERVs during development by its recruitment to their repetitive sequences through KRAB zinc-finger proteins (KZNFs), but little is known about the regulation of ERVs in adult tissues. We observed that KAP1 repression of HERVK14C was conserved in differentiated human cells and performed KAP1 knockout to obtain an overview of KAP1 function. Our results show that KAP1 represses ERVs (including HERV-T and HERV-S) and ZNF genes, both of which overlap with KAP1 binding sites and H3K9me3 in multiple cell types. Furthermore, this pathway is functionally conserved in adult human peripheral blood mononuclear cells. Cytosine methylation that acts on KAP1 regulated loci is necessary to prevent an interferon response, and KAP1-depletion leads to activation of some interferon-stimulated genes. Finally, loss of KAP1 leads to a decrease in H3K9me3 enrichment at ERVs and ZNF genes and an RNA-sensing response mediated through MAVS signaling. These data indicate that the KAP1-KZNF pathway contributes to genome stability and innate immune control in adult human cells.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Gifford, Dr Robert
Authors: Tie, C. H.C., Fernandes, L., Conde, L., Robbez-Masson, L., Sumner, R. P., Peacock, T., Rodriguez-Plata, M. T., Mickute, G., Gifford, R., Towers, G. J., Herrero, J., and Rowe, H. M.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:EMBO Reports
Publisher:EMBO Press
ISSN (Online):1469-3178
Published Online:30 July 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in EMBO Reports 19(10): e45000
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172630010Innate Immunity and Host Species Barriers (Programme 7)Massimo PalmariniMedical Research Council (MRC)MC_UU_12014/10III - Centre for Virus Research