Human Cytomegalovirus-induced Host Protein Citrullination is Crucial for Viral Replication

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jun 24

PMID 34162877

Citations 17

Authors

Gloria Griffante

Francesca Gugliesi

Selina Pasquero

Valentina DellOste

Matteo Biolatti

Ari J Salinger

Santanu Mondal

Paul R Thompson

Eranthie Weerapana

Robert J Lebbink

Jasper A Soppe

Thomas Stamminger

Virginie Girault

Andreas Pichlmair

Gabor Oroszlan

Donald M Coen

Marco De Andrea

Santo Landolfo

Affiliations

Soon will be listed here.

Abstract

Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation is implicated in the pathogenesis of various types of cancers and autoimmune diseases. Consistent with the ability of human cytomegalovirus (HCMV) to induce post-translational modifications of cellular proteins to gain a survival advantage, we show that HCMV infection of primary human fibroblasts triggers PAD-mediated citrullination of several host proteins, and that this activity promotes viral fitness. Citrullinome analysis reveals significant changes in deimination levels of both cellular and viral proteins, with interferon (IFN)-inducible protein IFIT1 being among the most heavily deiminated one. As genetic depletion of IFIT1 strongly enhances HCMV growth, and in vitro IFIT1 citrullination impairs its ability to bind to 5'-ppp-RNA, we propose that viral-induced IFIT1 citrullination is a mechanism of HCMV evasion from host antiviral resistance. Overall, our findings point to a crucial role of citrullination in subverting cellular responses to viral infection.

Citing Articles

Brain-Region-Specific Differences in Protein Citrullination/Deimination in a Pre-Motor Parkinson's Disease Rat Model.

Mercer A, Sancandi M, Maclatchy A, Lange S Int J Mol Sci. 2024; 25(20).

PMID: 39456949 PMC: 11509057. DOI: 10.3390/ijms252011168.

Targeting Peptidylarginine Deiminase 3 to Efficiently Suppress Herpes Simplex Virus Type 2 Infection.

Pasquero S, Gugliesi F, Biolatti M, Albano C, Bajetto G, Trifiro L Int J Mol Sci. 2024; 25(16).

PMID: 39201398 PMC: 11354815. DOI: 10.3390/ijms25168709.

The battle between host antiviral innate immunity and immune evasion by cytomegalovirus.

Li S, Xie Y, Yu C, Zheng C, Xu Z Cell Mol Life Sci. 2024; 81(1):341.

PMID: 39120730 PMC: 11335264. DOI: 10.1007/s00018-024-05369-y.

upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis.

Wu H, Yuan H, Zhang J, He T, Deng Y, Chen Y Ann Rheum Dis. 2024; 83(12):1666-1676.

PMID: 39107082 PMC: 11671999. DOI: 10.1136/ard-2023-225306.

Human cytomegalovirus and neonatal infection.

Lawrence S Curr Res Microb Sci. 2024; 7:100257.

PMID: 39070527 PMC: 11276932. DOI: 10.1016/j.crmicr.2024.100257.

References

Brinkman E, Chen T, Amendola M, van Steensel B . Easy quantitative assessment of genome editing by sequence trace decomposition. Nucleic Acids Res. 2014; 42(22):e168. PMC: 4267669. DOI: 10.1093/nar/gku936. View

Barlow P, Gwyer Findlay E, Currie S, Davidson D . Antiviral potential of cathelicidins. Future Microbiol. 2013; 9(1):55-73. DOI: 10.2217/fmb.13.135. View

Pratesi F, Tommasi C, Anzilotti C, Puxeddu I, Sardano E, Di Colo G . Antibodies to a new viral citrullinated peptide, VCP2: fine specificity and correlation with anti-cyclic citrullinated peptide (CCP) and anti-VCP1 antibodies. Clin Exp Immunol. 2011; 164(3):337-45. PMC: 3087929. DOI: 10.1111/j.1365-2249.2011.04378.x. View

Chen H, Beardsley G, Coen D . Mechanism of ganciclovir-induced chain termination revealed by resistant viral polymerase mutants with reduced exonuclease activity. Proc Natl Acad Sci U S A. 2014; 111(49):17462-7. PMC: 4267342. DOI: 10.1073/pnas.1405981111. View

Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijn P . Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods. 1988; 20(4):309-21. DOI: 10.1016/0166-0934(88)90134-6. View

Bicker K, Subramanian V, Chumanevich A, Hofseth L, Thompson P . Seeing citrulline: development of a phenylglyoxal-based probe to visualize protein citrullination. J Am Chem Soc. 2012; 134(41):17015-8. PMC: 3572846. DOI: 10.1021/ja308871v. View

Luganini A, Caposio P, Landolfo S, Gribaudo G . Phosphorothioate-modified oligodeoxynucleotides inhibit human cytomegalovirus replication by blocking virus entry. Antimicrob Agents Chemother. 2008; 52(3):1111-20. PMC: 2258505. DOI: 10.1128/AAC.00987-07. View

Trier N, Holm B, Heiden J, Slot O, Locht H, Lindegaard H . Antibodies to a strain-specific citrullinated Epstein-Barr virus peptide diagnoses rheumatoid arthritis. Sci Rep. 2018; 8(1):3684. PMC: 5829227. DOI: 10.1038/s41598-018-22058-6. View

Appleton B, Loregian A, Filman D, Coen D, Hogle J . The cytomegalovirus DNA polymerase subunit UL44 forms a C clamp-shaped dimer. Mol Cell. 2004; 15(2):233-44. DOI: 10.1016/j.molcel.2004.06.018. View

10.

Haller O, Staeheli P, Schwemmle M, Kochs G . Mx GTPases: dynamin-like antiviral machines of innate immunity. Trends Microbiol. 2015; 23(3):154-63. DOI: 10.1016/j.tim.2014.12.003. View

11.

Bicker K, Thompson P . The protein arginine deiminases: Structure, function, inhibition, and disease. Biopolymers. 2012; 99(2):155-63. PMC: 3507426. DOI: 10.1002/bip.22127. View

12.

Tilvawala R, Nguyen S, Maurais A, Nemmara V, Nagar M, Salinger A . The Rheumatoid Arthritis-Associated Citrullinome. Cell Chem Biol. 2018; 25(6):691-704.e6. PMC: 6014894. DOI: 10.1016/j.chembiol.2018.03.002. View

13.

Yuzhalin A . Citrullination in Cancer. Cancer Res. 2019; 79(7):1274-1284. DOI: 10.1158/0008-5472.CAN-18-2797. View

14.

Gariano G, DellOste V, Bronzini M, Gatti D, Luganini A, De Andrea M . The intracellular DNA sensor IFI16 gene acts as restriction factor for human cytomegalovirus replication. PLoS Pathog. 2012; 8(1):e1002498. PMC: 3266931. DOI: 10.1371/journal.ppat.1002498. View

15.

E X, Pickering M, Debatis M, Castillo J, Lagadinos A, Wang S . An E2F1-mediated DNA damage response contributes to the replication of human cytomegalovirus. PLoS Pathog. 2011; 7(5):e1001342. PMC: 3093362. DOI: 10.1371/journal.ppat.1001342. View

16.

Jackson S, Redeker A, Arens R, van Baarle D, van den Berg S, Benedict C . CMV immune evasion and manipulation of the immune system with aging. Geroscience. 2017; 39(3):273-291. PMC: 5505894. DOI: 10.1007/s11357-017-9986-6. View

17.

Ertl P, Powell K . Physical and functional interaction of human cytomegalovirus DNA polymerase and its accessory protein (ICP36) expressed in insect cells. J Virol. 1992; 66(7):4126-33. PMC: 241215. DOI: 10.1128/JVI.66.7.4126-4133.1992. View

18.

Loregian A, Appleton B, Hogle J, Coen D . Residues of human cytomegalovirus DNA polymerase catalytic subunit UL54 that are necessary and sufficient for interaction with the accessory protein UL44. J Virol. 2003; 78(1):158-67. PMC: 303418. DOI: 10.1128/jvi.78.1.158-167.2004. View

19.

Pichlmair A, Lassnig C, Eberle C, Gorna M, Baumann C, Burkard T . IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA. Nat Immunol. 2011; 12(7):624-30. DOI: 10.1038/ni.2048. View

20.

van Venrooij W, van Beers J, Pruijn G . Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol. 2011; 7(7):391-8. DOI: 10.1038/nrrheum.2011.76. View