DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway
Viral oncogenes remove the host's STING
Cancer-causing viruses, such as the human papilloma virus (HPV) that causes cervical cancer, account for 12% of human cancers. One way they can cause cancer is by targeting tumor suppressor proteins in the host. Now Lau et al. report that DNA tumor viruses can also thwart the host's immune system. Oncogenes from HPV and human adenovirus bound to the protein STING, a key component of the cGAS-STING pathway that senses and defends against intracellular DNA. In this way, the viruses subvert the host's antiviral immunity and set up shop, which, for an unlucky few, eventually causes cancer.
Science, this issue p. 568
Abstract
Cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, which is essential for blockade of the retinoblastoma tumor suppressor, is also important for antagonizing DNA sensing. E1A and E7 bind to STING, and silencing of these oncogenes in human tumor cells restores the cGAS-STING pathway. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes.
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Supplementary Material
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Materials and Methods
Figs. S1 and S2
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References and Notes
1
Goubau D., Deddouche S., Reis e Sousa C., Cytosolic sensing of viruses. Immunity 38, 855–869 (2013).
2
Paladino P., Mossman K. L., Mechanisms employed by herpes simplex virus 1 to inhibit the interferon response. J. Interferon Cytokine Res. 29, 599–608 (2009).
3
Doehle B. P., Chang K., Rustagi A., McNevin J., McElrath M. J., Gale M., Vpu mediates depletion of interferon regulatory factor 3 during HIV infection by a lysosome-dependent mechanism. J. Virol. 86, 8367–8374 (2012).
4
Meylan E., Curran J., Hofmann K., Moradpour D., Binder M., Bartenschlager R., Tschopp J., Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).
5
García-Sastre A., Induction and evasion of type I interferon responses by influenza viruses. Virus Res. 162, 12–18 (2011).
6
Sun L., Wu J., Du F., Chen X., Chen Z. J., Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).
7
Ishikawa H., Barber G. N., STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).
8
Stetson D. B., Ko J. S., Heidmann T., Medzhitov R., Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).
9
Stetson D. B., Medzhitov R., Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93–103 (2006).
10
Saito T., Owen D. M., Jiang F., Marcotrigiano J., Gale M., Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454, 523–527 (2008).
11
Graham F. L., Smiley J., Russell W. C., Nairn R., Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J. Gen. Virol. 36, 59–72 (1977).
12
Gey G. O., Coffman W. D., Kubicek M. T., Tissue culture studies of the proliferative capacity of cervical carcinoma and normal epithelium. Cancer Res. 12, 264 (1952).
13
Boshart M., Gissmann L., Ikenberg H., Kleinheinz A., Scheurlen W., zur Hausen H., A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J. 3, 1151–1157 (1984).
14
Moore P. S., Chang Y., Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat. Rev. Cancer 10, 878–889 (2010).
15
de Villiers E.-M., Schneider A., Miklaw H., Papendick U., Wagner D., Wesch H., Wahrendorf J., zur Hausen H., Human papillomavirus infections in women with and without abnormal cervical cytology. Lancet 330, 703–706 (1987).
16
Levine A. J., The common mechanisms of transformation by the small DNA tumor viruses: The inactivation of tumor suppressor gene products: p53. Virology 384, 285–293 (2009).
17
Bhattacharya S., Eckner R., Grossman S., Oldread E., Arany Z., D’Andrea A., Livingston D. M., Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha. Nature 383, 344–347 (1996).
18
Juang Y. T., Lowther W., Kellum M., Au W. C., Lin R., Hiscott J., Pitha P. M., Primary activation of interferon A and interferon B gene transcription by interferon regulatory factor 3. Proc. Natl. Acad. Sci. U.S.A. 95, 9837–9842 (1998).
19
Ronco L. V., Karpova A. Y., Vidal M., Howley P. M., Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev. 12, 2061–2072 (1998).
20
Fonseca G. J., Thillainadesan G., Yousef A. F., Ablack J. N., Mossman K. L., Torchia J., Mymryk J. S., Adenovirus evasion of interferon-mediated innate immunity by direct antagonism of a cellular histone posttranslational modification. Cell Host Microbe 11, 597–606 (2012).
21
Lowy D. R., Willumsen B. M., Function and regulation of ras. Annu. Rev. Biochem. 62, 851–891 (1993).
22
McLaughlin-Drubin M. E., Münger K., The human papillomavirus E7 oncoprotein. Virology 384, 335–344 (2009).
23
Corbeil H. B., Branton P. E., Functional importance of complex formation between the retinoblastoma tumor suppressor family and adenovirus E1A proteins as determined by mutational analysis of E1A conserved region 2. J. Virol. 68, 6697–6709 (1994).
24
Weinberg R. A., The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).
25
Sage J., Mulligan G. J., Attardi L. D., Miller A., Chen S., Williams B., Theodorou E., Jacks T., Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. Genes Dev. 14, 3037–3050 (2000).
26
Burdette D. L., Vance R. E., STING and the innate immune response to nucleic acids in the cytosol. Nat. Immunol. 14, 19–26 (2013).
27
Liu S., Cai X., Wu J., Cong Q., Chen X., Li T., Du F., Ren J., Wu Y. T., Grishin N. V., Chen Z. J., Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630 (2015).
28
Ahn K., Szczesna-Skorupa E., Kemper B., The amino-terminal 29 amino acids of cytochrome P450 2C1 are sufficient for retention in the endoplasmic reticulum. J. Biol. Chem. 268, 18726–18733 (1993).
29
Shalem O., Sanjana N. E., Hartenian E., Shi X., Scott D. A., Mikkelsen T. S., Heckl D., Ebert B. L., Root D. E., Doench J. G., Zhang F., Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84–87 (2014).
30
Hwang E. S., Riese D. J., Settleman J., Nilson L. A., Honig J., Flynn S., DiMaio D., Inhibition of cervical carcinoma cell line proliferation by the introduction of a bovine papillomavirus regulatory gene. J. Virol. 67, 3720–3729 (1993).
31
Ma Z., Jacobs S. R., West J. A., Stopford C., Zhang Z., Davis Z., Barber G. N., Glaunsinger B. A., Dittmer D. P., Damania B., Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc. Natl. Acad. Sci. U.S.A. 112, E4306–E4315 (2015).
32
de Souza R. F., Iyer L. M., Aravind L., Diversity and evolution of chromatin proteins encoded by DNA viruses. Biochim. Biophys. Acta 1799, 302–318 (2010).
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Science
Volume 350 | Issue 6260
30 October 2015
30 October 2015
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Copyright © 2015, American Association for the Advancement of Science.
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Submission history
Received: 10 April 2015
Accepted: 11 September 2015
Published in print: 30 October 2015
Acknowledgments
We are grateful to D. DiMaio for the BPV-E2 construct; to J. Kagan for the p450 ER-targeting motif; to J. Sage for providing the Rb/p107/p130 triple-knockout MEFs; and to members of the Stetson lab for discussions. The data presented in this paper are tabulated in the main paper and in the supplementary materials. D.B.S. is a scholar of the Rita Allen Foundation and a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease. E.E.G. is supported by a Cancer Research Institute Irvington postdoctoral fellowship.
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