Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses

Christian K. Holm; Stine H. Rahbek; Hans Henrik Gad; Rasmus O. Bak; Martin R. Jakobsen; Zhaozaho Jiang; Anne Louise Hansen; Simon K. Jensen; Chenglong Sun; Martin K. Thomsen; Anders Laustsen; Camilla G. Nielsen; Kasper Severinsen; Yingluo Xiong; Dara L. Burdette; Veit Hornung; Robert Jan Lebbink; Mogens Duch; Katherine A. Fitzgerald; Shervin Bahrami; Jakob Giehm Mikkelsen; Rune Hartmann; Søren R. Paludan

doi:10.1038/ncomms10680

Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses

Christian K. Holm, Stine H. Rahbek, Hans Henrik Gad, Rasmus O. Bak, Martin R. Jakobsen, Zhaozaho Jiang, Anne Louise Hansen, Simon K. Jensen, Chenglong Sun, Martin K. Thomsen, Anders Laustsen, Camilla G. Nielsen, Kasper Severinsen, Yingluo Xiong, Dara L. Burdette, Veit Hornung, Robert Jan Lebbink, Mogens Duch, Katherine A. Fitzgerald, Shervin BahramiJakob Giehm Mikkelsen, Rune Hartmann, Søren R. Paludan

Research output: Contribution to journal › Article › peer-review

154 Scopus citations

Abstract

Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.

Original language	English (US)
Article number	10680
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10680
State	Published - Feb 19 2016
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Holm, C. K., Rahbek, S. H., Gad, H. H., Bak, R. O., Jakobsen, M. R., Jiang, Z., Hansen, A. L., Jensen, S. K., Sun, C., Thomsen, M. K., Laustsen, A., Nielsen, C. G., Severinsen, K., Xiong, Y., Burdette, D. L., Hornung, V., Lebbink, R. J., Duch, M., Fitzgerald, K. A., ... Paludan, S. R. (2016). Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses. Nature communications, 7, Article 10680. https://doi.org/10.1038/ncomms10680

Holm, CK, Rahbek, SH, Gad, HH, Bak, RO, Jakobsen, MR, Jiang, Z, Hansen, AL, Jensen, SK, Sun, C, Thomsen, MK, Laustsen, A, Nielsen, CG, Severinsen, K, Xiong, Y, Burdette, DL, Hornung, V, Lebbink, RJ, Duch, M, Fitzgerald, KA, Bahrami, S, Mikkelsen, JG, Hartmann, R & Paludan, SR 2016, 'Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses', Nature communications, vol. 7, 10680. https://doi.org/10.1038/ncomms10680

@article{d50e3a3181754b86b8a3acf52ed47151,

title = "Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses",

abstract = "Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.",

author = "Holm, {Christian K.} and Rahbek, {Stine H.} and Gad, {Hans Henrik} and Bak, {Rasmus O.} and Jakobsen, {Martin R.} and Zhaozaho Jiang and Hansen, {Anne Louise} and Jensen, {Simon K.} and Chenglong Sun and Thomsen, {Martin K.} and Anders Laustsen and Nielsen, {Camilla G.} and Kasper Severinsen and Yingluo Xiong and Burdette, {Dara L.} and Veit Hornung and Lebbink, {Robert Jan} and Mogens Duch and Fitzgerald, {Katherine A.} and Shervin Bahrami and Mikkelsen, {Jakob Giehm} and Rune Hartmann and Paludan, {S{\o}ren R.}",

note = "Funding Information: Grant support for S.R.P., C.K.H. and M.R.J. was received from: Danish Council for Independent Research, Medical Research (12-124330; 0602-02914B; 0602-02669B; 4004-00237B), The Novo Nordisk Foundation, The Lundbeck Foundation (R34-3855; R151-2013-14443), Aase og Ejnar Danielsens Fond, Gigtforeningen, Oda og Hans Svenningsens Fond, Fonden til L{\ae}gevidenskabens Fremme, H{\o}rslevs Fond. Grant support for R.H. was received from: Danish Council for Independent Research, Medical Research (11-107588) and Danish Council for Independent Research, Natural Science (1323-00218). H.H.G. was supported by a fellowship from the Danish Council for Independent Research (12-132515). M.D. was supported by a grant from the Danish Council for Independent Research (1335-00170). R.J.L. was supported by Veni grant 916.10.138 from The Netherlands Organisation for Scientific Research and grant UU 2012-5667 from the Dutch Cancer Society. We thank K.S. Petersen and E. Kruse for technical assistance on cell work and CRISPR/Cas9 genome engineering, respectively.",

year = "2016",

month = feb,

day = "19",

doi = "10.1038/ncomms10680",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses

AU - Holm, Christian K.

AU - Rahbek, Stine H.

AU - Gad, Hans Henrik

AU - Bak, Rasmus O.

AU - Jakobsen, Martin R.

AU - Jiang, Zhaozaho

AU - Hansen, Anne Louise

AU - Jensen, Simon K.

AU - Sun, Chenglong

AU - Thomsen, Martin K.

AU - Laustsen, Anders

AU - Nielsen, Camilla G.

AU - Severinsen, Kasper

AU - Xiong, Yingluo

AU - Burdette, Dara L.

AU - Hornung, Veit

AU - Lebbink, Robert Jan

AU - Duch, Mogens

AU - Fitzgerald, Katherine A.

AU - Bahrami, Shervin

AU - Mikkelsen, Jakob Giehm

AU - Hartmann, Rune

AU - Paludan, Søren R.

N1 - Funding Information: Grant support for S.R.P., C.K.H. and M.R.J. was received from: Danish Council for Independent Research, Medical Research (12-124330; 0602-02914B; 0602-02669B; 4004-00237B), The Novo Nordisk Foundation, The Lundbeck Foundation (R34-3855; R151-2013-14443), Aase og Ejnar Danielsens Fond, Gigtforeningen, Oda og Hans Svenningsens Fond, Fonden til Lægevidenskabens Fremme, Hørslevs Fond. Grant support for R.H. was received from: Danish Council for Independent Research, Medical Research (11-107588) and Danish Council for Independent Research, Natural Science (1323-00218). H.H.G. was supported by a fellowship from the Danish Council for Independent Research (12-132515). M.D. was supported by a grant from the Danish Council for Independent Research (1335-00170). R.J.L. was supported by Veni grant 916.10.138 from The Netherlands Organisation for Scientific Research and grant UU 2012-5667 from the Dutch Cancer Society. We thank K.S. Petersen and E. Kruse for technical assistance on cell work and CRISPR/Cas9 genome engineering, respectively.

PY - 2016/2/19

Y1 - 2016/2/19

N2 - Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.

AB - Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.

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U2 - 10.1038/ncomms10680

DO - 10.1038/ncomms10680

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SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 10680

ER -

Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses

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