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Induction of transposable element expression is central to innate sensing

Derek C. Rookhuizen, Pierre-Emmanuel Bonte, Mengliang Ye, Thomas Hoyler, Matteo Gentili, Nina Burgdorf, Sylvère Durand, Fanny Aprahamian, Guido Kroemer, Nicolas Manel, Joshua J Waterfall, Richard Milne, Christel Goudot, Greg J. Towers, Sebastian Amigorena
doi: https://doi.org/10.1101/2021.09.10.457789
Derek C. Rookhuizen
1Institut Curie, PSL Research University, INSERM U932, Equipes Labellisées Ligue contre le Cancer, Paris, France, F-75005
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  • For correspondence: rookhuizenberkeley@gmail.com
Pierre-Emmanuel Bonte
1Institut Curie, PSL Research University, INSERM U932, Equipes Labellisées Ligue contre le Cancer, Paris, France, F-75005
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Mengliang Ye
1Institut Curie, PSL Research University, INSERM U932, Equipes Labellisées Ligue contre le Cancer, Paris, France, F-75005
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Thomas Hoyler
1Institut Curie, PSL Research University, INSERM U932, Equipes Labellisées Ligue contre le Cancer, Paris, France, F-75005
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Matteo Gentili
1Institut Curie, PSL Research University, INSERM U932, Equipes Labellisées Ligue contre le Cancer, Paris, France, F-75005
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Nina Burgdorf
1Institut Curie, PSL Research University, INSERM U932, Equipes Labellisées Ligue contre le Cancer, Paris, France, F-75005
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Sylvère Durand
2Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
3Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
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Fanny Aprahamian
2Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
3Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
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Guido Kroemer
4Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
5Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
6Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
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Nicolas Manel
1Institut Curie, PSL Research University, INSERM U932, Equipes Labellisées Ligue contre le Cancer, Paris, France, F-75005
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Joshua J Waterfall
7INSERM U830, Integrative Functional Genomics of Cancer Lab, PSL Research University, Institut Curie Research Center; Paris, France
8Department of Translational Research, PSL Research University, Institut Curie Research Center; Paris, France
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Richard Milne
9Division of Infection and Immunity, University College London; London, United Kingdom
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Christel Goudot
1Institut Curie, PSL Research University, INSERM U932, Equipes Labellisées Ligue contre le Cancer, Paris, France, F-75005
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Greg J. Towers
9Division of Infection and Immunity, University College London; London, United Kingdom
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Sebastian Amigorena
1Institut Curie, PSL Research University, INSERM U932, Equipes Labellisées Ligue contre le Cancer, Paris, France, F-75005
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SUMMARY

Evidence indicates that transposable elements (TEs) stimulate innate sensing pathways in various pathologies but it is not clear whether they are sensed during normal physiological responses. Here we show that, during activation with an exogenous pathogen associated molecular pattern (PAMP), dendritic cells (DCs) epigenetically remodel heterochromatin at TEs by depleting the methyltransferase Suv39h1 and reducing histone-3 lysine-9 trimethylation (H3K9me3). TLR4 signaling activates TE expression to enhance innate responses through the DNA sensor cGAS. Cytosolic cGAS-bound DNA comprised LINE1 TEs as the predominant endogenous ligands. Concordantly, LINE1 inhibition attenuated the type-I IFN response to LPS and rescued influenza virus infection. We propose that in healthy cells, exogenous PAMPs epigenetically activate self-derived PAMPs (LINE1) that engage cGAS to enhance responses. These data explain why pathogens employ redundant and broad innate immune countermeasures, to suppress activation of host PAMPs and illustrate a hitherto unappreciated role for host genome-derived PAMPs in response to pathogens.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 11, 2021.
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Induction of transposable element expression is central to innate sensing
Derek C. Rookhuizen, Pierre-Emmanuel Bonte, Mengliang Ye, Thomas Hoyler, Matteo Gentili, Nina Burgdorf, Sylvère Durand, Fanny Aprahamian, Guido Kroemer, Nicolas Manel, Joshua J Waterfall, Richard Milne, Christel Goudot, Greg J. Towers, Sebastian Amigorena
bioRxiv 2021.09.10.457789; doi: https://doi.org/10.1101/2021.09.10.457789
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Induction of transposable element expression is central to innate sensing
Derek C. Rookhuizen, Pierre-Emmanuel Bonte, Mengliang Ye, Thomas Hoyler, Matteo Gentili, Nina Burgdorf, Sylvère Durand, Fanny Aprahamian, Guido Kroemer, Nicolas Manel, Joshua J Waterfall, Richard Milne, Christel Goudot, Greg J. Towers, Sebastian Amigorena
bioRxiv 2021.09.10.457789; doi: https://doi.org/10.1101/2021.09.10.457789

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