Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Virology Journal
Published in: Virology Journal 1/2019

Open Access 01-12-2019 | Adenovirus | Research

NAD-linked mechanisms of gene de-repression and a novel role for CtBP in persistent adenovirus infection of lymphocytes

Authors: Megan L. Dickherber, Charlie Garnett-Benson

Published in: Virology Journal | Issue 1/2019

Login to get access

Abstract

Background

Adenovirus (AdV) infection is ubiquitous in the human population and causes acute infection in the respiratory and gastrointestinal tracts. In addition to lytic infections in epithelial cells, AdV can persist in a latent form in mucosal lymphocytes, and nearly 80% of children contain viral DNA in the lymphocytes of their tonsils and adenoids. Reactivation of latent AdV is thought to be the source of deadly viremia in pediatric transplant patients. Adenovirus latency and reactivation in lymphocytes is not well studied, though immune cell activation has been reported to promote productive infection from latency. Lymphocyte activation induces global changes in cellular gene expression along with robust changes in metabolic state. The ratio of free cytosolic NAD+/NADH can impact gene expression via modulation of transcriptional repressor complexes. The NAD-dependent transcriptional co-repressor C-terminal Binding Protein (CtBP) was discovered 25 years ago due to its high affinity binding to AdV E1A proteins, however, the role of this interaction in the viral life cycle remains unclear.

Methods

The dynamics of persistently- and lytically-infected cells are evaluated. RT-qPCR is used to evaluate AdV gene expression following lymphocyte activation, treatment with nicotinamide, or disruption of CtBP-E1A binding.

Results

PMA and ionomycin stimulation shifts the NAD+/NADH ratio in lymphocytic cell lines and upregulates viral gene expression. Direct modulation of NAD+/NADH by nicotinamide treatment also upregulates early and late viral transcripts in persistently-infected cells. We found differential expression of the NAD-dependent CtBP protein homologs between lymphocytes and epithelial cells, and inhibition of CtBP complexes upregulates AdV E1A expression in T lymphocyte cell lines but not in lytically-infected epithelial cells.

Conclusions

Our data provide novel insight into factors that can regulate AdV infections in activated human lymphocytes and reveal that modulation of cellular NAD+/NADH can de-repress adenovirus gene expression in persistently-infected lymphocytes. In contrast, disrupting the NAD-dependent CtBP repressor complex interaction with PxDLS-containing binding partners paradoxically alters AdV gene expression. Our findings also indicate that CtBP activities on viral gene expression may be distinct from those occurring upon metabolic alterations in cellular NAD+/NADH ratios or those occurring after lymphocyte activation.
Literature
1.
2.
Garnett CT, Talekar G, Mahr JA, et al. Latent species C adenoviruses in human tonsil tissues. J Virol. 2009;83:2417–28.PubMedCrossRef
3.
4.
Thounaojam AD, Balakrishnan A, Mun AB. Detection and molecular typing of human adenoviruses associated with respiratory illnesses in Kerala. Jpn J Infect Dis. 2016;69:500–4.PubMedCrossRef
5.
6.
EVANS AS. Latent adenovirus infections of the human respiratory tract. Am J Hyg. 1958;67:256–66.PubMed
7.
HOGG JC. Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med. 2001;164:S71–5.PubMedCrossRef
8.
Kosulin K, Geiger E, Vécsei A, et al. Persistence and reactivation of human adenoviruses in the gastrointestinal tract. Clinical Microbiology and Infection. 2016;22:381.e1–8.CrossRef
9.
Kosulin K, Berkowitsch B, Matthes S, et al. Intestinal adenovirus shedding before allogeneic stem cell transplantation is a risk factor for invasive infection post-transplant. EBioMedicine. 2018;28:114–9.PubMedPubMedCentralCrossRef
10.
Mynarek M, Ganzenmueller T, Mueller-Heine A, et al. Patient, virus, and treatment-related risk Factorsin pediatric adenovirus infection after stem cell transplantation: results of a routine monitoring program. Biol Blood Marrow Transplant. 2014;20:250–6.PubMedCrossRef
11.
Wurzel DF, Mackay IM, Marchant JM, et al. Adenovirus species C is associated with chronic Suppurative lung diseases in children. Clin Infect Dis. 2014;59:34–40.PubMedCrossRef
12.
Kampmann B, Cubitt D, Walls T, et al. Improved outcome for children with disseminated adenoviral infection following allogeneic stem cell transplantation. Br J Haematol. 2005;130:595–603.PubMedCrossRef
13.
DSouza A, Fretham C. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides, 2018 [Internet]. CIBMTR. Available from: https://​www.​cibmtr.​org, [cited 2019 30 Aug ].
14.
15.
Lee YJ, Prockop SE, Papanicolaou GA. Approach to adenovirus infections in the setting of hematopoietic cell transplantation. Curr Opin Infect Dis. 2017;30:377–87.PubMedCrossRef
16.
Fox JP, Brandt CD, Wassermann FE, et al. The virus watch program: a continuing surveillance of viral infections in metropolitan New York families. VI. Observations of adenovirus infections: virus excretion patterns, antibody response, efficiency of surveillance, patterns of infections, and relation to illness. Am J Epidemiol. 1969;89:25–50.PubMedCrossRef
17.
18.
Markel D, Lam E, Harste G, et al. Type dependent patterns of human adenovirus persistence in human T-lymphocyte cell lines. J Med Virol. 2014;86:785–94.PubMedCrossRef
19.
Krzywkowski T, Ciftci S, Assadian F, et al. Simultaneous single-cell In Situ analysis of human adenovirus type 5 DNA and mRNA expression patterns in lytic and persistent infection. J Virol. 2017;91:e00166–17.PubMedPubMedCentralCrossRef
20.
Furuse Y, Ornelles DA, Cullen BR. Persistently adenovirus-infected lymphoid cells express microRNAs derived from the viral VAI and especially VAII RNA. Virology. 2013;447:140–5.PubMedCrossRef
21.
Murali VK, Ornelles DA, Gooding LR, et al. Adenovirus death protein (ADP) is required for lytic infection of human lymphocytes. J Virol. 2014;88:903–12.PubMedPubMedCentralCrossRef
22.
Racioppi L, Means AR. Calcium/calmodulin-dependent kinase IV in immune and inflammatory responses: novel routes for an ancient traveller. Trends Immunol. 2008;29:600–7.PubMedCrossRef
23.
Giberson AN, Davidson AR, Parks RJ. Chromatin structure of adenovirus DNA throughout infection. Nucleic Acids Res. 2012;40:2369–76.PubMedCrossRef
24.
Matsumoto K, Okuwaki M, Kawase H, et al. Stimulation of DNA transcription by the replication factor from the adenovirus genome in a chromatin-like structure. J Biol Chem. 1998;270:9645–50.CrossRef
25.
Okuwaki M, Nagata K. Template activating factor-I remodels the chromatin structure and stimulates transcription from the chromatin template*. J Biol Chem. 1998;273:34511–8.PubMedCrossRef
26.
Boyd JM, Subramanian T, Schaeper U, et al. A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis. EMBO J. 1993;12:469–78.PubMedPubMedCentralCrossRef
27.
Schaeper U, Boyd JM, Verma S, et al. Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation. Proc Natl Acad Sci U S A. 1995;92:10467–71.PubMedPubMedCentralCrossRef
28.
Stankiewicz TR, Gray JJ, Winter AN, et al. C-terminal binding proteins: central players in development and disease. Biomolecular Concepts. 2014;5:489–511.PubMedCrossRef
29.
Sewalt RGAB, Gunster MJ, van der Vlag J, et al. C-terminal binding protein is a transcriptional repressor that interacts with a specific class of vertebrate Polycomb proteins. Mol Cell Biol. 1999;19:777–87.PubMedPubMedCentralCrossRef
30.
31.
Shi Y, Sawada J-I, Sui G, et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003;422:735–8.PubMedCrossRef
32.
Zhang Q, Piston DW, Goodman RH. Regulation of Corepressor function by nuclear NADH. Science. 2002;295:1895–7.PubMed
33.
Kumar V, Carlson JE, Ohgi KA, et al. Transcription Corepressor CtBP is an NAD+-regulated dehydrogenase. Mol Cell. 2002;10:857–69.PubMedCrossRef
34.
Mani-Telang P, Sutrias-Grau M, Williams G, et al. Role of NAD binding and catalytic residues in the C-terminal binding protein corepressor. FEBS Lett. 2007;581:5241–6.PubMedCrossRef
35.
Shen Y, Kapfhamer D, Minnella AM, et al. Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP. Nat Commun. 2017:1–13.
36.
Deng Y, Li H, Yin X, et al. C-terminal binding protein 1 modulates cellular redox via feedback regulation of MPC1 and MPC2 in melanoma cells. Med Sci Monit. 2018;24:7614–24.PubMedPubMedCentralCrossRef
37.
Pelka P, Ablack JNG, Fonseca GJ, et al. Intrinsic structural disorder in adenovirus E1A: a viral molecular hub linking multiple diverse processes. J Virol. 2008;82:7252–63.PubMedPubMedCentralCrossRef
38.
Bruton RK, Pelka P, Mapp KL, et al. Identification of a second CtBP binding site in adenovirus type 5 E1A conserved region 3. J Virol. 2008;82:8476–86.PubMedPubMedCentralCrossRef
39.
Subramanian T, Zhao L-J, Chinnadurai G. Interaction of CtBP with adenovirus E1A suppresses immortalization of primary epithelial cells and enhances virus replication during productive infection. Virology. 2013;443:313–20.PubMedCrossRef
40.
Zemke NR, Berk AJ. The Adenovirus E1A C Terminus Suppresses a Delayed Antiviral Response and Modulates RAS Signaling. Cell Host Microbe. 2017;22:789–800.e5.PubMedPubMedCentralCrossRef
41.
Subramanian T, La Regina M, Chinnadurai G. Enhanced ras oncogene mediated cell transformation and tumorigenesis by adenovirus 2 mutants lacking the C-terminal region of E1a protein. Oncogene. 1989;4:415–20.PubMed
42.
Subramanian T, Malstrom SE, Chinnadurai G. Requirement of the C-terminal region of adenovirus E1a for cell transformation in cooperation with E1b. Oncogene. 1991;6:1171–3.PubMed
43.
Cohen MJ, Yousef AF, Massimi P, et al. Dissection of the C-terminal region of E1A redefines the roles of CtBP and other cellular targets in oncogenic transformation. J Virol. 2013;87:10348–55.PubMedPubMedCentralCrossRef
44.
Zhao L-J, Subramanian T, Chinnadurai G. Changes in C-terminal binding protein 2 (CtBP2) Corepressor complex induced by E1A and modulation of E1A transcriptional activity by CtBP2. J Biol Chem. 2006;281:36613–23.PubMedCrossRef
45.
Zhao L-J, Subramanian T, Zhou Y, et al. Acetylation by p300 regulates nuclear localization and function of the transcriptional Corepressor CtBP2. J Biol Chem. 2006;281:4183–9.PubMedCrossRef
46.
Zhao L-J, Subramanian T, Vijayalingam S, et al. PLDLS-dependent interaction of E1A with CtBP: regulation of CtBP nuclear localization and transcriptional functions. Oncogene. 2007;26:7544–51.PubMedPubMedCentralCrossRef
47.
Klein G, Lindahl T, Jondal M, et al. Continuous lymphoid cell lines with characteristics of B cells (bone-marrow-derived), lacking the Epstein-Barr virus genome and derived from three human lymphomas. Proc Natl Acad Sci. 1974;71:3283–6.PubMedCrossRefPubMedCentral
48.
Bett AJ, Krougliak V, Graham FL. DNA sequence of the deletion/insertion in early region 3 of Ad5 dl309. Virus Res. 1995;39:75–82.PubMedCrossRef
49.
McNees AL, Mahr JA, Ornelles D, et al. Postinternalization inhibition of adenovirus gene expression and infectious virus production in human T-cell lines. J Virol. 2004;78:6955–66.PubMedPubMedCentralCrossRef
50.
51.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25:402–8.CrossRefPubMed
52.
53.
Berk AJ. Adenoviridae. In: Knipe DM, Howley PM, editor(s). Fields Virology, 6th Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2013. p. 1704–1731.
54.
55.
Nevins JR, Ginsberg HS, Blanchard JM, et al. Regulation of the primary expression of the early adenovirus transcription units. J Virol. 1979;32:727–33.PubMedPubMedCentral
56.
Logan JS, Shenk T. Transcriptional and translational control of adenovirus gene expression. Microbiol Rev. 1982;46:377–83.PubMedPubMedCentral
57.
Shipkova M, Wieland E. Surface markers of lymphocyte activation and markers of cell proliferation. Clin Chim Acta. 2012;413:1338–49.PubMedCrossRef
58.
Gai Q, James CBL. Identification of a region on the adenovirus E1A gene responsible for induction by Phorbol Ester tumor promoter. In Vitro Cellular Developmental Biology. 2001;37:465–70.PubMedCrossRef
59.
Buckbinder L, Miralles VJ, Reinberg D. TPA can overcome the requirement for EIa and together act synergistically in stimulating expression of the adenovirus EIII promoter. EMBO J. 1989;8:4239–50.PubMedPubMedCentralCrossRef
60.
Scharer CD, Barwick BG, Youngblood BA, et al. Global DNA methylation remodeling accompanies CD8 T cell effector function. J Immunol. 2013;191:3419–29.PubMedCrossRef
61.
Scharer CD, Bally APR, Gandham B, et al. Cutting edge: chromatin accessibility programs CD8 T cell memory. J Immunol. 2017;198:2238–43.PubMedCrossRef
62.
63.
Berger NA, Berger SJ, Sikorski GW, et al. Amplification of pyridine nucleotide pools in mitogen-stimulated human lymphocytes. Exp Cell Res. 1982;137:79–88.PubMedCrossRef
64.
65.
Prusinkiewicz MA, Mymryk JS. Metabolic reprogramming of the host cell by human adenovirus infection. Viruses. 2019;11:141–21.PubMedCentralCrossRef
66.
Santidrian AF, Matsuno-Yagi A, Ritland M, et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest. 2013;123:1068–81.PubMedPubMedCentralCrossRef
67.
68.
Gooding LR, Aquino L, Duerksen-Hughes PJ, et al. The E1B 19,000-molecular-weight protein of group C adenoviruses prevents tumor necrosis factor cytolysis of human cells but not of mouse cells. J Virol. 1991;65:3083–94.PubMedPubMedCentral
69.
Gomez-Gutierrez JG, Nitz J, Sharma R, et al. Combined therapy of oncolytic adenovirus and temozolomide enhances lung cancer virotherapy in vitro and in vivo. Virology. 2016;487:249–59.PubMedCrossRef
70.
Blevins MA, Kouznetsova J, Krueger AB, et al. Small molecule, NSC95397, inhibits the CtBP1-protein partner interaction and CtBP1-mediated transcriptional repression. J Biomol Screen. 2015;20:663–72.PubMedCrossRef
71.
Rodríguez E, Ip WH, Kolbe V, et al. Humanized mice reproduce acute and persistent human adenovirus infection. J Infect Dis. 2017;215:70–9.PubMedCrossRef
72.
Greiner EF, Guppy M, Brand K. Essential for proliferation and the glycolytic enzyme induction that ProvokeasTransition to glycolytic energy production. J Biol Chem. 1994;269:31484–90.PubMed
73.
74.
Hwang ES, Song SB. Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Cell Mol Life Sci. 2017;74:3347–62.PubMedCrossRef
75.
Zhang X, Liu J, Cao X. Metabolic control of T-cell immunity via epigenetic mechanisms. Cell Mol Immunol. 2018;15:203–5.PubMedCrossRef
76.
Almeida L, Lochner M, Berod L, et al. Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol. 2016;28:514–24.PubMedCrossRef
77.
Chinnadurai G. CtBP, an Unconventional Transcriptional Corepressor in Development and Oncogenesis. Molecular Cell. 9:213–24.PubMedCrossRef
78.
Madison DL, Wirz JA, Siess D, et al. Nicotinamide adenine dinucleotide-induced Multimerization of the co-repressor CtBP1 relies on a switching tryptophan. J Biol Chem. 2013;288:27836–48.PubMedPubMedCentralCrossRef
79.
Subramanian T, Chinnadurai G. Association of class I histone deacetylases with transcriptional corepressor CtBP. FEBS Lett. 2003;540:255–8.PubMedCrossRef
80.
Sollerbrandt K, Chinnadurai G, Svensson C. The CtBP binding domain in the adenovirus E1Aprotein controls CR1-dependent transactivation. Nucleic Acids Res. 1996;24:2578–84.CrossRef
81.
Ebert O, Finke S, Salahi A, et al. Lymphocyte apoptosis: induction by gene transfer techniques. Gene Ther. 1997;4:296–302.PubMedCrossRef
82.
Zhao Y, Zheng Z, Cohen CJ, et al. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. Mol Ther. 2005;13:151–9.PubMedCrossRef
83.
Lin X, Sun B, Liang M, et al. Opposed regulation of Corepressor CtBP by SUMOylation and PDZ binding. Mol Cell. 2003;11:1389–96.PubMedCrossRef
84.
Bergman LM, Morris L, Darley M, et al. Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins. BMC Cell Biol. 2006;7.PubMedPubMedCentralCrossRef
85.
Criqui-Filipe P, Ducret C, Maira S-M, et al. Net, a negative Ras-switchable TCF, contains a second inhibition domain, the CID, that mediates repression through interactions with CtBP and de-acetylation. EMBO J. 1999;18:3392–403.PubMedPubMedCentralCrossRef
86.
Alpatov R, Munguba GC, Caton P, et al. Nuclear speckle-associated protein Pnn/DRS binds to the transcriptional corepressor CtBP and relieves CtBP-mediated repression of the E-cadherin gene. Mol Cell Biol. 2004;24:10223–35.PubMedPubMedCentralCrossRef
87.
Zheng Y, Stamminger T, Hearing P. E2F/Rb family proteins mediate interferon induced repression of adenovirus immediate early transcription to promote persistent viral infection. PLoS Pathog. 2016;12:e1005415–24.PubMedPubMedCentralCrossRef
88.
Koyuncu E, Budayeva HG, Miteva YV, et al. Sirtuins Are Evolutionarily Conserved Viral Restriction Factors mBio. 2014;5:e02249–14.
89.
Matias AA, Serra AT, Silva AC, et al. Portuguese winemaking residues as a potential source of natural anti-adenoviral agents. Int J Food Sci Nutr. 2010;61:357–68.PubMedCrossRef
90.
Picchione KE, Bhattacharjee A. Viral genome silencing by neuronal sirtuin 1. J Neuro-Oncol. 2010;17:184–8.
91.
Nebenzahl-Sharon K, Sharf R, Amer J, et al. An interaction with PARP-1 and inhibition of Parylation contribute to attenuation of DNA damage signaling by the adenovirus E4orf4 protein. J Virol. 2019;93:738–20.
92.
Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly (ADP-ribose) and PARPs. 2012:1–14.
93.
Kraus WL. Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Curr Opin Cell Biol. 2008;20:294–302.PubMedPubMedCentralCrossRef
Metadata
Title
NAD-linked mechanisms of gene de-repression and a novel role for CtBP in persistent adenovirus infection of lymphocytes
Authors
Megan L. Dickherber
Charlie Garnett-Benson
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Adenovirus
Published in
Virology Journal / Issue 1/2019
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-019-1265-y

Other articles of this Issue 1/2019

Virology Journal 1/2019 Go to the issue

Short report

Development of a duplex SYBR Green I-based quantitative real-time PCR assay for the rapid differentiation of goose and Muscovy duck parvoviruses

Review

Coronavirus envelope protein: current knowledge

Research

Important roles of C-terminal residues in degradation of capsid protein of classical swine fever virus

Research

Effect of human pegivirus route of transmission on the genetic distribution of the virus: an institution based cross-sectional study

Research

Functional analysis of apple stem pitting virus coat protein variants

Research

Viral respiratory tract infections in young children with cystic fibrosis: a prospective full-year seasonal study

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24 to hear Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits