Human cytomegalovirus-induced host protein citrullination is crucial for viral replication
Griffante, Gloria; Gugliesi, Francesca; Pasquero, Selina; Dell'Oste, Valentina; Biolatti, Matteo; Salinger, Ari J; Mondal, Santanu; Thompson, Paul R; Weerapana, Eranthie; Lebbink, Robert J; Soppe, Jasper A; Stamminger, Thomas; Girault, Virginie; Pichlmair, Andreas; Oroszlán, Gábor; Coen, Donald M; De Andrea, Marco; Landolfo, Santo
(2021) Nature Communications, volume 12, issue 1, pp. 1 - 14
(Article)
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
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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.
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Keywords: Adaptor Proteins, Signal Transducing/metabolism, Animals, Cells, Cultured, Chlorocebus aethiops, Citrullination, Cytomegalovirus/metabolism, DNA-Binding Proteins/metabolism, Fibroblasts/cytology, HEK293 Cells, Host-Pathogen Interactions, Humans, Myxovirus Resistance Proteins/metabolism, Protein Processing, Post-Translational, Protein-Arginine Deiminases/metabolism, RNA-Binding Proteins/metabolism, Vero Cells, Viral Proteins/metabolism, Virus Replication, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Research Support, Non-U.S. Gov't, Journal Article, Research Support, N.I.H., Extramural
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We are grateful to Davide Gibellini for HIV FACS analysis, Han Chen for providing GST-UL54, and Jean Pesola for advice on statistical analysis. We thank Marcello Arsura for critically reviewing the manuscript. This research was supported by the European Commission under the Horizon2020 program (H2020-MSCA-ITN-2015) (S.L.), the Italian Ministry of Education, University and Research-MIUR (PRIN 20178ALPCM) (V. D.O.), “Cassa di Risparmio” Foundation of Turin (RF = 2019.2273) (V.D.O.), the Compagnia San Paolo of Turin (IFIBD) (M.D.A.), the AGING Project—Department of Excellence—Department of Translational Medicine, University of Piemonte Orientale (G.G.) and the University of Turin (RILO1801) (RILO1901) (S.L.) (M.D.A.) (V.D.O.) (F. G.) (M.B.). Work in the Thompson lab is funded by the National Institute of General Medical Sciences (R35GM118112) and National Institute of Health (F32GM128231). Work in the Coen lab was supported by the National Institute of Allergy and Infectious Diseases (R56AI019838 and R21AI141940). Work in the Pichlmair lab is funded by the ERC consolidator grant (ERC-CoG ProDAP, 817798) and the German Research Foundation (TRR179/TP11, TRR237/A07). Work in Stamminger lab is funded by the Deutsche Forschungsgemeinschaft (DFG) (STA357/7-1). Publisher Copyright: © 2021, The Author(s).
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