TY - JOUR
T1 - Human cytomegalovirus-induced host protein citrullination is crucial for viral replication
AU - Griffante, Gloria
AU - Gugliesi, Francesca
AU - Pasquero, Selina
AU - Dell'Oste, Valentina
AU - Biolatti, Matteo
AU - Salinger, Ari J
AU - Mondal, Santanu
AU - Thompson, Paul R
AU - Weerapana, Eranthie
AU - Lebbink, Robert J
AU - Soppe, Jasper A
AU - Stamminger, Thomas
AU - Girault, Virginie
AU - Pichlmair, Andreas
AU - Oroszlán, Gábor
AU - Coen, Donald M
AU - De Andrea, Marco
AU - Landolfo, Santo
N1 - 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).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing/metabolism
KW - Animals
KW - Cells, Cultured
KW - Chlorocebus aethiops
KW - Citrullination
KW - Cytomegalovirus/metabolism
KW - DNA-Binding Proteins/metabolism
KW - Fibroblasts/cytology
KW - HEK293 Cells
KW - Host-Pathogen Interactions
KW - Humans
KW - Myxovirus Resistance Proteins/metabolism
KW - Protein Processing, Post-Translational
KW - Protein-Arginine Deiminases/metabolism
KW - RNA-Binding Proteins/metabolism
KW - Vero Cells
KW - Viral Proteins/metabolism
KW - Virus Replication
UR - https://www.scopus.com/pages/publications/85108370610
U2 - 10.1038/s41467-021-24178-6
DO - 10.1038/s41467-021-24178-6
M3 - Article
C2 - 34162877
SN - 2041-1723
VL - 12
SP - 1
EP - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3910
ER -