Human cytomegalovirus-induced host protein citrullination is crucial for viral replication

Gloria Griffante, Francesca Gugliesi, Selina Pasquero, Valentina Dell’Oste, Matteo Biolatti, Ari J. Salinger, Santanu Mondal, Paul R. Thompson, Eranthie Weerapana, Robert J. Lebbink, Jasper A. Soppe, Thomas Stamminger, Virginie Girault, Andreas Pichlmair, Gábor Oroszlán, Donald M. Coen, Marco De Andrea () and Santo Landolfo ()
Additional contact information
Gloria Griffante: University of Turin
Francesca Gugliesi: University of Turin
Selina Pasquero: University of Turin
Valentina Dell’Oste: University of Turin
Matteo Biolatti: University of Turin
Ari J. Salinger: UMass Medical School
Santanu Mondal: UMass Medical School
Paul R. Thompson: UMass Medical School
Eranthie Weerapana: Boston College
Robert J. Lebbink: University Medical Center Utrecht
Jasper A. Soppe: University Medical Center Utrecht
Thomas Stamminger: Ulm University Medical Center
Virginie Girault: Technical University of Munich
Andreas Pichlmair: Technical University of Munich
Gábor Oroszlán: Blavatnik Institute, Harvard Medical School
Donald M. Coen: Blavatnik Institute, Harvard Medical School
Marco De Andrea: University of Turin
Santo Landolfo: University of Turin

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24178-6

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