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IFN-Stimulated Genes Through ATR Kinase Simian Virus 40 Large T Antigen Induces

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IFN-Stimulated Genes Through ATR Kinase Simian Virus 40 Large T Antigen Induces Simian Virus 40 Large T Antigen Induces IFN-Stimulated Genes through ATR Kinase Adriana Forero, Nicholas S. Giacobbi, Kevin D. McCormick, Ole V. Gjoerup, Christopher J. Bakkenist, This information is current as James M. Pipas and Saumendra N. Sarkar of September 29, 2021. J Immunol 2014; 192:5933-5942; Prepublished online 5 May 2014; doi: 10.4049/jimmunol.1303470 http://www.jimmunol.org/content/192/12/5933 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/05/03/jimmunol.130347 Material 0.DCSupplemental http://www.jimmunol.org/ References This article cites 60 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/192/12/5933.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 29, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Simian Virus 40 Large T Antigen Induces IFN-Stimulated Genes through ATR Kinase Adriana Forero,*,† Nicholas S. Giacobbi,‡ Kevin D. McCormick,*,† Ole V. Gjoerup,*,†,1 Christopher J. Bakkenist,x James M. Pipas,‡ and Saumendra N. Sarkar*,† Polyomaviruses encode a large T Ag (LT), a multifunctional protein essential for the regulation of both viral and host cell gene expression and productive viral infection. Previously, we have shown that stable expression of LT protein results in upregulation of genes involved in the IFN induction and signaling pathway. In this study, we focus on the cellular signaling mechanism that leads to the induction of IFN responses by LT. Our results show that ectopic expression of SV40 LT results in the induction of IFN- stimulated genes (ISGs) in human fibroblasts and confers an antiviral state. We describe a LT-initiated DNA damage response (DDR) that activates IFN regulatory factor 1, causing IFN-b production and consequent ISG expression in human cells. This IFN-b and ISG induction is dependent on ataxia-telangiectasia mutated and Rad3-related (ATR) kinase, but independent of ATM. Downloaded from ATR kinase inhibition using a selective kinase inhibitor (ETP-46464) caused a decrease in IFN regulatory factor 1 stabilization and ISG expression. Furthermore, expression of a mutant LT that does not induce DDR also does not induce IFN-b and ISGs. These results show that, in the absence of viral infection, LT-initiated activation of ATR-dependent DDR is sufficient for the induction of an IFN-b–mediated innate immune response in human cells. Thus, we have uncovered a novel and critical role for ATR as a mediator of antiviral responses utilizing LT. The Journal of Immunology, 2014, 192: 5933–5942. http://www.jimmunol.org/ he polyomavirus (PyV) family consists of small dsDNA proteins, large T Ag (LT), small t Ag, 17k T (early region), and late viruses that infect a wide variety of hosts. Infection with PyV proteins with structural and auxiliary functions. The SV40 LT is T is ubiquitous among the human population and generally a well-studied multifunctional protein that controls viral DNA repli- results in subclinical infections in healthy hosts. However, upon the cation, host cell proliferation, and gene expression, thereby promoting onset of AIDS-related, age-related, and iatrogenic immune suppres- cellular transformation. These functions are largely mediated by sion, manifestations of clinical disease associated with viral infection interactions between LT and numerous cellular proteins (4). Identi- become apparent (1–3). To date, there are few successful therapies for fying the cellular processes targeted by LT is crucial for under- the treatment of human PyV-related diseases. Thus, understanding the standing the pathogenesis of PyV and their transformative phenotype. by guest on September 29, 2021 interactions between the virus and the host response to viral infection Genotoxic stress triggers a signaling cascade, called DNA damage is crucial for the development of new effective therapies. response (DDR), mediated by the kinases ataxia-telangiectasia The wealth of knowledge of PyV biology has stemmed from mutated (ATM) and ATM and Rad3-related (ATR) (5). Activation studies utilizing the prototypic virus, SV40. SV40 encodes early of these kinases by dsDNA breaks and ssDNA gaps, respectively, results in the induction of the checkpoint proteins and modifications *Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA of many other proteins implicated in DNA repair to maintain ge- 15213; †Department of Microbiology and Molecular Genetics, University of Pittsburgh nome integrity and cell survival (6). Multiple studies have provided School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213; ‡Department of x evidence that infection with mouse PyV virus (7), JC PyV (8), BK Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15213; and Department of Radiation Oncology, University of Pittsburgh School of Medicine, University of Pittsburgh, PyV (9), and SV40 (10–14) causes the activation of DDR to aug- Pittsburgh, PA 15213 ment viral genome replication. It has also been shown that ex- 1Current address: Molecular Oncology Research Institute, Tufts Medical Center, pression of SV40 LT protein alone is sufficient to activate both Boston, MA. ATM and ATR in cells (12). However, the cellular consequences of Received for publication December 31, 2013. Accepted for publication April 16, this DDR activation are not completely understood. 2014. Detection of viral infection triggers cytoplasmic and nuclear This work was supported in part by National Institute of Allergy and Infectious Diseases Grant AI082673 (to S.N.S.), National Institutes of Health Grant RO1 sensors that initiate a signaling cascade that results in the induction 98956 (to J.M.P.), and National Institutes of Health Grant RO1CA148644 (to of type I IFN and the expression of IFN-stimulated genes (ISGs). C.J.B.). This work used the University of Pittsburgh Cancer Institute core facilities The ISGs have antiviral effector functions that limit the replication and was supported in part by Award P30CA047904 from the National Cancer Institute. of viral genomes, inhibit protein synthesis, and promote cell death Address correspondence and reprint requests to Dr. Saumendra N. Sarkar, University (15). Previously, using mouse genome-wide arrays, we reported of Pittsburgh Cancer Institute, Hillman Cancer Research Pavilion, Suite 1.8, 5117 that SV40 LT expression results in a tissue-specific induction of Centre Avenue, Pittsburgh, PA 15213. E-mail address: [email protected] ISGs (16). Although this phenomenon was dependent on various The online version of this article contains supplemental material. domains of LT (17), it was surprising to find ISG induction in the Abbreviations used in this article: ATM, ataxia-telangiectasia mutated; ATR, ATM absence of an active virus infection. Furthermore, the host factors and Rad3-related; CHX, cycloheximide; DDR, DNA damage response; dl, deletion; responsible for this phenomenon remained elusive. EMCV, encephalomyocarditis virus; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; LT, large T Ag; m.o.i., multiplicity of infection; p(I):(C), polyinosinic:polycytidylic In this study, we have examined the cellular signaling pathways acid; PyV, polyomavirus; qRT-PCR, quantitative RT-PCR; SeV, Sendai virus; shRNA, that are responsible for the SV40 LT-mediated induction of ISGs in short hairpin RNA; siRNA, small interfering RNA; VSV, vesicular stomatitis virus. human fibroblasts. LT expression induced upregulation of IFN Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 regulatory factor (IRF)1 protein, causing transcription and secre- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1303470 5934 T Ag INDUCES ISGs THROUGH ATR KINASE tion of IFN-b and its downstream genes through IFN receptor VSV-GFP (m.o.i. 1), HSV-1 (K26) at a m.o.i. 5, or EMCV (m.o.i. 5). signaling. Furthermore, we showed that the induction of DDR by Infected cell supernatants were harvested at the indicated time points and 2 LT is needed to induce the expression of IRF1, in an ATR kinase kept at 80˚C until further use. Infectious virus production was measured by plaque assay and reported as PFU/ml. Alternatively, BJ/TERT LT cells activity-dependent manner. Therefore, our data provide a clear were pretreated with CHX (50 ng/ml), washed twice with PBS, and in- mechanistic link between the DDR with the regulation of IFN cubated with 4 mm ETP-46464 or DMSO for 3 h prior to infection with responses and the induction of innate immune gene expression in EMCV (m.o.i. 50). Virus growth was quantified by plaque assay on Vero the absence of viral infection. cells and expressed as PFU/ml. Cellular viability was determined by crystal violet staining. Materials and Methods IRF3 dimerization assays Cells and reagents BJ/TERT, BJ/TERT VECTOR, and BJ/TERT LT cells (1 3 106) were HEK293T (Invitrogen, Carlsbad, CA; catalogue R700-07) cell lines were plated in 10-cm plates. BJ/TERT cells were infected with 300 hemag- cultured in DMEM (Lonza, Basel, Switzerland) supplemented with 10% glutinating units/ml Sendai virus (SeV) for 8 h. Cells were washed with FBS (Atlanta Biologicals, Flowery Branch, GA) and 100 IU/ml penicillin PBS and lysed in 70 ml lysis buffer (50 mM Tris-HCl [pH 7.5], 150 mM and 100 mg/ml streptomycin (Pen/Strep; Lonza). BJ/TERT cells (12) and NaCl, 1 mM EDTA, 1% Nonidet P-40, 2 mM Na3VO4, 10 mM NaF, and derived cell lines were cultured in DMEM with 20% medium 199 (Invi- 12 mM b-glycerophosphate).
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