Cellular Requirements for Sensing and Elimination of Incoming HSV-1 DNA and Capsids

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Cellular Requirements for Sensing and Elimination of Incoming HSV-1 DNA and Capsids. / Sun, Chenglong; Luecke, Stefanie; Bodda, Chiranjeevi; Jønsson, Kasper L.; Cai, Yujia; Zhang, Bao Cun; Jensen, Søren B.; Nordentoft, Iver; Jensen, Jacob M.; Jakobsen, Martin R.; Paludan, Sren R.

In: Journal of Interferon and Cytokine Research, Vol. 39, No. 4, 2019, p. 191-204.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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Sun, Chenglong et al. "Cellular Requirements for Sensing and Elimination of Incoming HSV-1 DNA and Capsids". Journal of Interferon and Cytokine Research. 2019, 39(4). 191-204. https://doi.org/10.1089/jir.2018.0141

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Sun, Chenglong ; Luecke, Stefanie ; Bodda, Chiranjeevi ; Jønsson, Kasper L. ; Cai, Yujia ; Zhang, Bao Cun ; Jensen, Søren B. ; Nordentoft, Iver ; Jensen, Jacob M. ; Jakobsen, Martin R. ; Paludan, Sren R. / Cellular Requirements for Sensing and Elimination of Incoming HSV-1 DNA and Capsids. In: Journal of Interferon and Cytokine Research. 2019 ; Vol. 39, No. 4. pp. 191-204.

Bibtex

@article{29e121b62fba443e8ddd35b46d17fb55,
title = "Cellular Requirements for Sensing and Elimination of Incoming HSV-1 DNA and Capsids",
abstract = "Incoming viruses challenge the cell with diverse foreign molecules, which need to be sensed quickly to initiate immune responses and to remove the viral components. In this study, we investigate the cellular requirements for sensing and degradation of incoming viral DNA and capsids during herpes simplex virus type 1 (HSV-1) infections. Using click chemistry labeling of the viral genome, we found that HSV-1 DNA was released from a subset of capsids into the cytosol early in infection. By next-generation sequencing of cyclic GMP-AMP (cGAMP) synthase (cGAS)-bound DNA from HSV-1-infected cells, we show that HSV-1 DNA was bound by the cytosolic DNA sensor cGAS. Activation of cGAS enzymatic activity by viral DNA did not require proteasomal activity, indicating that viral DNA release into the cytosol is not proteasome-dependent. However, induction of interferon (IFN)-β expression was blocked by inhibition of the proteasome, suggesting a contribution of the proteasome to IFN-β induction through the cGAS-stimulator of interferon genes pathway. Viral DNA was cleared from the cytosol within few hours, in a manner dependent on TREX1 and a cGAS-dependent process. Capsid material in the cytoplasm was also degraded rapidly. This was partially blocked by treatment with a proteasome inhibitor. This treatment led to accumulation of DNA-containing viral capsids near the nucleus and reduced nuclear entry of viral DNA. Thus, cells infected with HSV-1 use a panel of mechanisms to eliminate viral DNA and capsids. This represents a barrier for establishment of infection and potentially enables the host to gear the IFN-β response to a level required for antiviral defense without causing immunopathology.",
keywords = "cGAS-STING, DNA sensing, herpes simplex virus",
author = "Chenglong Sun and Stefanie Luecke and Chiranjeevi Bodda and J{\o}nsson, {Kasper L.} and Yujia Cai and Zhang, {Bao Cun} and Jensen, {S{\o}ren B.} and Iver Nordentoft and Jensen, {Jacob M.} and Jakobsen, {Martin R.} and Paludan, {Sren R.}",
year = "2019",
doi = "10.1089/jir.2018.0141",
language = "English",
volume = "39",
pages = "191--204",
journal = "Journal of Interferon & Cytokine Research",
issn = "1079-9907",
publisher = "Mary AnnLiebert, Inc. Publishers",
number = "4",

}

RIS

TY - JOUR

T1 - Cellular Requirements for Sensing and Elimination of Incoming HSV-1 DNA and Capsids

AU - Sun, Chenglong

AU - Luecke, Stefanie

AU - Bodda, Chiranjeevi

AU - Jønsson, Kasper L.

AU - Cai, Yujia

AU - Zhang, Bao Cun

AU - Jensen, Søren B.

AU - Nordentoft, Iver

AU - Jensen, Jacob M.

AU - Jakobsen, Martin R.

AU - Paludan, Sren R.

PY - 2019

Y1 - 2019

N2 - Incoming viruses challenge the cell with diverse foreign molecules, which need to be sensed quickly to initiate immune responses and to remove the viral components. In this study, we investigate the cellular requirements for sensing and degradation of incoming viral DNA and capsids during herpes simplex virus type 1 (HSV-1) infections. Using click chemistry labeling of the viral genome, we found that HSV-1 DNA was released from a subset of capsids into the cytosol early in infection. By next-generation sequencing of cyclic GMP-AMP (cGAMP) synthase (cGAS)-bound DNA from HSV-1-infected cells, we show that HSV-1 DNA was bound by the cytosolic DNA sensor cGAS. Activation of cGAS enzymatic activity by viral DNA did not require proteasomal activity, indicating that viral DNA release into the cytosol is not proteasome-dependent. However, induction of interferon (IFN)-β expression was blocked by inhibition of the proteasome, suggesting a contribution of the proteasome to IFN-β induction through the cGAS-stimulator of interferon genes pathway. Viral DNA was cleared from the cytosol within few hours, in a manner dependent on TREX1 and a cGAS-dependent process. Capsid material in the cytoplasm was also degraded rapidly. This was partially blocked by treatment with a proteasome inhibitor. This treatment led to accumulation of DNA-containing viral capsids near the nucleus and reduced nuclear entry of viral DNA. Thus, cells infected with HSV-1 use a panel of mechanisms to eliminate viral DNA and capsids. This represents a barrier for establishment of infection and potentially enables the host to gear the IFN-β response to a level required for antiviral defense without causing immunopathology.

AB - Incoming viruses challenge the cell with diverse foreign molecules, which need to be sensed quickly to initiate immune responses and to remove the viral components. In this study, we investigate the cellular requirements for sensing and degradation of incoming viral DNA and capsids during herpes simplex virus type 1 (HSV-1) infections. Using click chemistry labeling of the viral genome, we found that HSV-1 DNA was released from a subset of capsids into the cytosol early in infection. By next-generation sequencing of cyclic GMP-AMP (cGAMP) synthase (cGAS)-bound DNA from HSV-1-infected cells, we show that HSV-1 DNA was bound by the cytosolic DNA sensor cGAS. Activation of cGAS enzymatic activity by viral DNA did not require proteasomal activity, indicating that viral DNA release into the cytosol is not proteasome-dependent. However, induction of interferon (IFN)-β expression was blocked by inhibition of the proteasome, suggesting a contribution of the proteasome to IFN-β induction through the cGAS-stimulator of interferon genes pathway. Viral DNA was cleared from the cytosol within few hours, in a manner dependent on TREX1 and a cGAS-dependent process. Capsid material in the cytoplasm was also degraded rapidly. This was partially blocked by treatment with a proteasome inhibitor. This treatment led to accumulation of DNA-containing viral capsids near the nucleus and reduced nuclear entry of viral DNA. Thus, cells infected with HSV-1 use a panel of mechanisms to eliminate viral DNA and capsids. This represents a barrier for establishment of infection and potentially enables the host to gear the IFN-β response to a level required for antiviral defense without causing immunopathology.

KW - cGAS-STING

KW - DNA sensing

KW - herpes simplex virus

UR - http://www.scopus.com/inward/record.url?scp=85064075354&partnerID=8YFLogxK

U2 - 10.1089/jir.2018.0141

DO - 10.1089/jir.2018.0141

M3 - Journal article

VL - 39

SP - 191

EP - 204

JO - Journal of Interferon & Cytokine Research

JF - Journal of Interferon & Cytokine Research

SN - 1079-9907

IS - 4

ER -